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Sample records for 111ll iiiii iiiii

  1. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 10 Table 10 to Subpart IIIII of Part... monitoring plan in lieu of a promulgated performance specification for a mercury concentration CMS. §...

  2. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 10 Table 10 to Subpart IIIII of Part... monitoring plan in lieu of a promulgated performance specification for a mercury concentration CMS. §...

  3. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 10 Table 10 to Subpart IIIII of Part... monitoring plan in lieu of a promulgated performance specification for a mercury concentration CMS. §...

  4. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 10 Table 10 to Subpart IIIII of Part... monitoring plan in lieu of a promulgated performance specification for a mercury concentration CMS. §...

  5. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 10 Table 10 to Subpart IIIII of Part... monitoring plan in lieu of a promulgated performance specification for a mercury concentration CMS. §...

  6. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action immediately... mercury seal pot stopper securely in place. 6. Cell room floors Month Cracks, spalling, or...

  7. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 14 2013-07-01 2013-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  8. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... other deficiency in a cell room floor, pillar, or beam that could cause liquid mercury to become trapped.... f. If you take a cell off line or isolate the leaking equipment, the date and time you take the...

  9. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 14 2012-07-01 2011-07-01 true Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  10. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 14 2014-07-01 2014-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  11. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... following as part of your plan . . . 1. Center aisles of cell rooms A description of the manner of washdown... baskets 6. Hydrogen system piping 7. Basement floor of cell rooms 8. Tanks 9. Pillars and beams in...

  12. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action immediately... mercury seal pot stopper securely in place. 6. Cell room floors Month Cracks, spalling, or...

  13. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action immediately... mercury seal pot stopper securely in place. 6. Cell room floors Month Cracks, spalling, or...

  14. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... other deficiency in a cell room floor, pillar, or beam that could cause liquid mercury to become trapped.... f. If you take a cell off line or isolate the leaking equipment, the date and time you take the...

  15. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... other deficiency in a cell room floor, pillar, or beam that could cause liquid mercury to become trapped.... f. If you take a cell off line or isolate the leaking equipment, the date and time you take the...

  16. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... following as part of your plan . . . 1. Center aisles of cell rooms A description of the manner of washdown... baskets 6. Hydrogen system piping 7. Basement floor of cell rooms 8. Tanks 9. Pillars and beams in...

  17. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... following as part of your plan . . . 1. Center aisles of cell rooms A description of the manner of washdown... baskets 6. Hydrogen system piping 7. Basement floor of cell rooms 8. Tanks 9. Pillars and beams in...

  18. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action...

  19. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action...

  20. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... vent hose; open-top container where liquid mercury is not covered by an aqueous liquid; end box...

  1. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... vent hose; open-top container where liquid mercury is not covered by an aqueous liquid; end box...

  2. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  3. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... rooms 10. Mercury cell repair areas 11. Maintenance shop areas 12. Work tables 13. Mercury...

  4. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  5. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... rooms 10. Mercury cell repair areas 11. Maintenance shop areas 12. Work tables 13. Mercury...

  6. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  7. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  8. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  9. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  10. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  11. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Problem Identification, Leak Detection and Mercury Vapor 6 Table 6 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII..., Leak Detection and Mercury Vapor As stated in Tables 1 and 2 of Subpart IIIII, examples of...

  12. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Problem Identification, Leak Detection and Mercury Vapor 6 Table 6 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII..., Leak Detection and Mercury Vapor As stated in Tables 1 and 2 of Subpart IIIII, examples of...

  13. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... be maintained under negative pressure. b. Keep each mercury pump tank closed, except when maintenance..., Operation, and Maintenance Requirements 1 Table 1 to Subpart IIIII of Part 63 Protection of Environment... Subpart IIIII of Part 63—Work Practice Standards—Design, Operation, and Maintenance Requirements As...

  14. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 5 Table 5 to Subpart IIIII of Part 63—Required Elements of Floor-Level Mercury Vapor...

  15. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 5 Table 5 to Subpart IIIII of Part 63—Required Elements of Floor-Level Mercury Vapor...

  16. Cholinergic suppression of excitatory synaptic transmission in layers II/III of the parasubiculum.

    PubMed

    Glasgow, S D; Glovaci, I; Karpowicz, L S; Chapman, C A

    2012-01-10

    Layer II of the parasubiculum (PaS) receives excitatory synaptic input from the CA1 region of the hippocampus and sends a major output to layer II of the medial and lateral entorhinal cortex. The PaS also receives heavy cholinergic innervation from the medial septum, which contributes to the generation of theta-frequency (4-12 Hz) electroencephalographic (EEG) activity. Cholinergic receptor activation exerts a wide range of effects in other areas of the hippocampal formation, including membrane depolarization, changes in neuronal excitability, and suppression of excitatory synaptic responses. The present study was aimed at determining how cholinergic receptor activation modulates excitatory synaptic input to the layer II/III neurons of the PaS in acute brain slices. Field excitatory postsynaptic potentials (fEPSPs) in layer II/III of the PaS were evoked by stimulation of either layer I afferents, or ascending inputs from layer V. Bath-application of the cholinergic agonist carbachol (0.5-10 μM) suppressed the amplitude of fEPSPs evoked by both superficial- and deep layer stimulation, and also enhanced paired-pulse facilitation. Constant bath-application of the GABA(A) antagonist bicuculline (10 μM) failed to eliminate the suppression, indicating that the cholinergic suppression of fEPSPs is not due to increased inhibitory tone. The muscarinic receptor antagonist atropine (1 μM) blocked the suppression of fEPSPs, and the selective M(1)-preferring receptor antagonist pirenzepine (1 μM), but not the M(2)-preferring antagonist methoctramine (1-5 μM), also significantly attenuated the suppression. Therefore, cholinergic receptor activation suppresses excitatory synaptic input to layer II/III neurons of the PaS, and this suppression is mediated in part by M(1) receptor activation.

  17. A modified varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong; Vandemeulebroecke, Marc

    2016-07-01

    Conventionally, adaptive phase II/III clinical trials are carried out with a strict two-stage design. Recently, a varying-stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another endpoint can be switched as the primary endpoint. However, in many therapeutic areas, the primary study endpoint is well established. Therefore, we modify this design to consider one study endpoint only so that it may be more readily applicable in real clinical trial designs. Our simulations show that, the same as the original design, this modified design controls the Type I error rate, and the design parameters such as the threshold probability for the two-stage setting and the alpha allocation ratio in the two-stage setting versus the three-stage setting have a great impact on the design characteristics. However, this modified design requires a larger sample size for the initial stage, and the probability of futility becomes much higher when the threshold probability for the two-stage setting gets smaller. Copyright © 2016 John Wiley & Sons, Ltd.

  18. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  19. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  20. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  1. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 3 Table 3 to Subpart IIIII of Part 63—Work Practice... that you cannot repair the leaking equipment without taking the cell off line, provided that...

  2. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 3 Table 3 to Subpart IIIII of Part 63—Work Practice... that you cannot repair the leaking equipment without taking the cell off line, provided that...

  3. Risk of node metastasis of sentinel lymph nodes detected in level II/III of the axilla by single-photon emission computed tomography/computed tomography

    PubMed Central

    SHIMA, HIROAKI; KUTOMI, GORO; SATOMI, FUKINO; MAEDA, HIDEKI; TAKAMARU, TOMOKO; KAMESHIMA, HIDEKAZU; OMURA, TOSEI; MORI, MITSURU; HATAKENAKA, MASAMITSU; HASEGAWA, TADASHI; HIRATA, KOICHI

    2014-01-01

    In breast cancer, single-photon emission computed tomography/computed tomography (SPECT/CT) shows the exact anatomical location of sentinel nodes (SN). SPECT/CT mainly exposes axilla and partly exposes atypical sites of extra-axillary lymphatic drainage. The mechanism of how the atypical hot nodes are involved in lymphatic metastasis was retrospectively investigated in the present study, particularly at the level II/III region. SPECT/CT was performed in 92 clinical stage 0-IIA breast cancer patients. Sentinel lymph nodes are depicted as hot nodes in SPECT/CT. Patients were divided into two groups: With or without hot node in level II/III on SPECT/CT. The existence of metastasis in level II/III was investigated and the risk factors were identified. A total of 12 patients were sentinel lymph node biopsy metastasis positive and axillary lymph node dissection (ALND) was performed. These patients were divided into two groups: With and without SN in level II/III, and nodes in level II/III were pathologically proven. In 11 of the 92 patients, hot nodes were detected in level II/III. There was a significant difference in node metastasis depending on whether there were hot nodes in level II/III (P=0.0319). Multivariate analysis indicated that the hot nodes in level II/III and lymphatic invasion were independent factors associated with node metastasis. There were 12 SN-positive patients followed by ALND. In four of the 12 patients, hot nodes were observed in level II/III. Two of the four patients with hot nodes depicted by SPECT/CT and metastatic nodes were pathologically evident in the same lesion. Therefore, the present study indicated that the hot node in level II/III as depicted by SPECT/CT may be a risk of SN metastasis, including deeper nodes. PMID:25289038

  4. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII...; cracks or spalling in cell room floors, pillars, or beams; caustic leaks; liquid mercury accumulations or... through a detection cell where ultraviolet light at 253.7 nanometers (nm) is directed...

  5. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII...; cracks or spalling in cell room floors, pillars, or beams; caustic leaks; liquid mercury accumulations or... through a detection cell where ultraviolet light at 253.7 nanometers (nm) is directed...

  6. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII...; cracks or spalling in cell room floors, pillars, or beams; caustic leaks; liquid mercury accumulations or... through a detection cell where ultraviolet light at 253.7 nanometers (nm) is directed...

  7. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 1 Table 1 to... that are resistant to absorption of mercury, resistant to corrosion, facilitate the detection of liquid mercury spills or accumulations, and are easy to clean. b. Limit access around and beneath mercury...

  8. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 1 Table 1 to... that are resistant to absorption of mercury, resistant to corrosion, facilitate the detection of liquid mercury spills or accumulations, and are easy to clean. b. Limit access around and beneath mercury...

  9. A varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong

    2014-04-15

    Currently, adaptive phase II/III clinical trials are typically carried out with a strict two-stage design. The first stage is a learning stage called phase II, and the second stage is a confirmatory stage called phase III. Following phase II analysis, inefficacious or harmful dose arms are dropped, then one or two promising dose arms are selected for the second stage. However, there are often situations in which researchers are in dilemma to make 'go or no-go' decision and/or to select 'best' dose arm(s), as data from the first stage may not provide sufficient information for their decision making. In this case, it is challenging to follow a strict two-stage plan. Therefore, we propose a varying-stage adaptive phase II/III clinical trial design, in which we consider whether there is a need to have an intermediate stage to obtain more data, so that a more informative decision could be made. Hence, the number of further investigational stages in our design is determined on the basis of data accumulated to the interim analysis. With respect to adaptations, we consider dropping dose arm(s), switching another plausible endpoint as the primary study endpoint, re-estimating sample size, and early stopping for futility. We use an adaptive combination test to perform final analyses. By applying closed testing procedure, we control family-wise type I error rate at the nominal level of α in the strong sense. We delineate other essential design considerations including the threshold parameters and the proportion of alpha allocated in the two-stage versus three-stage setting.

  10. ROTATION OF THE K3 II-III GIANT STAR {alpha} HYDRA

    SciTech Connect

    Gray, David F.

    2013-08-01

    Fundamental spectroscopic determination of projected rotation rates of slowly rotating stars is challenging because the rotational broadening of the spectral lines is often comparable to, or smaller than, the broadening from other sources, most notably macroturbulence. Fourier techniques have the advantage over direct profile matching when the observed profiles are complete, but when the profiles are severely blended, the Fourier analysis is compromised. A process of modeling partial profiles for determining the rotation rate for stars having blended spectral lines is investigated and applied to the evolved star {alpha} Hya (K3 II-III). Projected rotation higher than 5 km s{sup -1} can be definitively ruled out for this star. Not all lines are equally good, depending on the amount of blending and also depending on the strength of the line, as the balance between the thermal and non-thermal components changes. A modest ambiguity arises between macroturbulence and rotational broadening, but a careful look at the differences between the observations and the models allows one to measure the rotation with acceptable precision. The result for {alpha} Hya is v sin i = 2.6 {+-} 0.3 km s{sup -1}.

  11. Detection of methicillin-resistant Staphylococcus pseudintermedius ST169 and novel ST354 SCCmec II-III isolates related to the worldwide ST71 clone.

    PubMed

    Ishihara, K; Koizumi, A; Saito, M; Muramatsu, Y; Tamura, Y

    2016-01-01

    The recent appearance of methicillin-resistant Staphylococcus pseudintermedius (MRSP) is a concern for both veterinary and human healthcare. MRSP clonal lineages with sequence type (ST) 71-spa t02-staphylococcal cassette chromosome mec (SCCmec) II-III and ST68-spa t06-SCCmec V have spread throughout Europe and North America, respectively. The current study compared the molecular characteristics of 43 MRSP isolates from dogs in Japan with those of MRSP from previous reports using multilocus sequence typing based on seven housekeeping genes, SCCmec typing, and detection of antimicrobial resistance genes. Three related clonal lineages, ST71, ST169, and the newly registered ST354, were observed in SCCmec II-III isolates from Japan, despite MRSP SCCmec II-III isolates being thought to belong to a single clonal lineage. The majority of SCCmec II-III isolates belonging to ST169 (9/11) and ST354 (3/3), but not ST71 (0/11), harboured tetM. Four STs were observed for the SCCmec V isolates; however, neither ST68 nor related STs were found in the Japanese MRSP isolates. In conclusion, MRSP SCCmec II-III isolates from Japan belonged to ST71 and related STs (ST169 and ST354). A variety of MRSP SCCmec V clones, including some novel clones, were identified.

  12. Evidence of active tectonics on a Roman aqueduct system (II-III century A.D.) near Rome, Italy

    NASA Astrophysics Data System (ADS)

    Marra, Fabrizio; Montone, Paola; Pirro, Mario; Boschi, Enzo

    2004-04-01

    In this paper we describe evidence of strong tectonic deformation affecting two aqueducts of Roman age (II-III century A.D.). The channels are located approximately 20 km northeast of Rome along the ancient Via Tiburtina. Brittle and ductile deformation affects these two structures, including extensional joint systems, NE-oriented faults, and horizontal distortion. This deformation is consistent with right-lateral movement on major N-striking faults, and represents the first evidence that tectonic deformation took place in historical times in the vicinity of Rome, with local strike-slip movement superimposed on a regional extensional fault system.

  13. Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex

    PubMed Central

    Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

    2016-01-01

    Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats—while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. PMID:27193420

  14. [Characteristic of inflammatory infiltrate of gastric mucosa in patients with grade II-III gastric dysplasia and of stomach cancer].

    PubMed

    Evtushenko, V A; Vusik, M V; Karakeshisheva, M B; Pleshko, R I; Ermolaeva, L A

    2008-01-01

    The study included 85 inpatients and outpatients in whom composition of inflammatory infiltrate from gastric mucosa (GM) was determined at the Oncological Research Institute, Tomsk Research Centre of the Siberian Division, Russian Academy of Medical Sciences. The patients were allocated to 4 groups depending on nosological form of the disease. Group 1 comprised 21 patients with grade II-III GM epithelial dysplasia, group 2 - 24 patients having stomach cancer (histologically confirmed adenocarcinoma), group 3 - 19 patients with stage II-III mucinous gastric carcinoma, group 4 - 20 allegedly healthy subjects without signs of gastrointestinal pathology. It was shown that dysplastic processes in GM are associated with an increase of neutrophil, eosinophil, macrophage, and mast cell count along with a drop in the number of lymphocytes and plasmocytes. Stroma of invasive stomach cancer underwent intense inflammatory infiltration accompanied by a rise in the number of lymphocytes, plasmocytes, and neutrophils. Mucinous gastric carcinoma was characterized by an increase of the number of neutrophils and macrophages. Patients having adenocarcinoma of the stomach showed enhanced plasmocytic infiltration by plasmocytes with a low number of eosinophils and mast cells. It is concluded that characteristics of inflammatory GM infiltrate may be useful for the objective assessment of stomach cancer risk in patients with GM dysplasia, formation of a high oncological risk group, adequate dynamic monitoring and treatment of these patients.

  15. Prognostic value of tumor infiltrating NK cells and macrophages in stage II+III esophageal cancer patients

    PubMed Central

    Zheng, Xiao; Shi, Liangrong; Wu, Changping; Jiang, Jingting

    2016-01-01

    The detailed understanding of the immunobiology of tumor microenvironment has recently translated into new therapeutic approach against human cancers. Besides the role of immune cells mediating adaptive immune responses, the tumor infiltrating components of the innate immune system including, neutrophils, mast cells, NK cells, and macrophages, also role importantly in anti-tumor immunity. In our present study, we retrospectively analyzed the prognostic value of the densities of tumor infiltrating NK cells and macrophages in esophageal cancer tissues derived from stage II+III patients. Our results showed that the density of the infiltrating NK cells in tumor stroma was significantly associated with nodal status. In addition, the densities of the infiltrating NK cells in tumor nest, and the infiltrating macrophages in tumor nest as well as in tumor stroma, were significantly associated with patients' postoperative prognoses. Furthermore, the combination of infiltrating NK cells in tumor nest and stroma, or the combination of infiltrating macrophages in tumor nest and stroma, could also be used as important prognostic tool in predicting the survival of the stage II+III esophageal cancer patients. PMID:27736796

  16. Composition and anion ordering in some Fe II-III hydroxysalt green rusts (carbonate, oxalate, methanoate): The fougerite mineral

    NASA Astrophysics Data System (ADS)

    Génin, Jean-Marie R.; Ruby, Christian

    2008-03-01

    Main features of Fe II-III hydroxysalts (green rusts) are obtained from XRD. Moreover, Mössbauer spectroscopy revealed that several Fe II sites exist. The structure is classified in green rusts one and two (GR1 and GR2) according to the stacking sequence of Fe(OH) 2 brucite-like layers depending on the shape and type of anions inserted within interlayers. Long range order as determined for hydroxysulphate GR2(SO 42-) is extended to distributions of cations and anions within GR1s even though these are not observed by XRD. Abundances of Fe II and Fe III environments within GR1s that intercalate carbonate, oxalate and methanoate (formate) are found for compositions [Fe 6IIFe 2III(OH) 16] 2+·[CO 32-·5H 2O] 2-, [Fe 4IIFe 2III(OH) 12] 2+·[CO 32-·3H 2O] 2-, [Fe 6IIFe 2III(OH) 16] 2+·[C 2O 42-·4H 2O] 2- and [Fe 5IIFe 2III(OH) 14] 2+·[2HCOO -·3H 2O] 2-, which correspond to orders α, β and γ where the cation distances are (2 × a0), (√3 × a0) or a mixture of both, with a ferric molar ratio x = {[Fe III]/[Fe total]} = 1/4, 1/3 and 2/7, respectively. Anion distributions within interlayers are devised and long range orders in other layered double hydroxides could questionably be extended from these models. The formula [Fe 6II(1- x) Fe 6 xIIIO 12H 2(7-3 x) ] 2+·[CO 32-·3H 2O] 2- for the fougerite mineral, which is the oxyhydroxycarbonate obtained by deprotonation of Fe II-III hydroxycarbonate [Fe 4IIFe 2III(OH) 12] 2+·[CO 32-·3H 2O] 2- where x ∈ [1/3,2/3] is confirmed.

  17. Reducing the Time From Diagnosis to Treatment of Patients With Stage II/III Rectal Cancer at a Large Public Hospital

    PubMed Central

    Leslie, Lori A.; Jacobs, Ryan W.; Millas, Stefanos; Surabhi, Venkateswar; Mok, Henry; Jhaveri, Pavan; Kott, Marylee M.; Jackson, Lymesia; Rieber, Alyssa; Bhadkamkar, Nishin A.

    2016-01-01

    Curative-intent therapy for stage II/III rectal cancer is necessarily complex. Current guidelines by the National Comprehensive Cancer Network recommend preoperative concurrent chemoradiation followed by resection and additional adjuvant chemotherapy. We used standard quality improvement methodology to implement a cost-effective intervention that reduced the time from diagnosis to treatment of patients with stage II/III rectal cancer by approximately 30% in a large public hospital in Houston, Texas. Implementation of the program resulted in a reduction in time from pathologic diagnosis to treatment of 29% overall, from 62 to 44 days. These gains were cost neutral and resulted from improvements in scheduling and coordination of care alone. Our results suggest that: (1) quality improvement methodology can be successfully applied to multidisciplinary cancer care, (2) effective interventions can be cost neutral, and (3) effective strategies can overcome complexities such as having multiple sites of care, high staff turnover, and resource limitations. PMID:26869658

  18. High expression of the stem cell marker nestin is an adverse prognostic factor in WHO grade II-III astrocytomas and oligoastrocytomas

    PubMed Central

    Hatanpaa, Kimmo J.; Foong, Chan; Raisanen, Jack M.; Oliver, Dwight; Hiemenz, Matthew C.; Burns, Dennis K.; White, Charles L.; Whitworth, L. Anthony; Mickey, Bruce; Stegner, Martha; Habib, Amyn A.; Fink, Karen; Maher, Elizabeth A.; Bachoo, Robert M.

    2015-01-01

    Infiltrating astrocytomas and oligoastrocytomas of low to anaplastic grade (WHO grades II and III), in spite of being associated with a wide range of clinical outcomes, can be difficult to subclassify and grade by the current histopathologic criteria. Unlike oligodendrogliomas and anaplastic oligodendrogliomas that can be identified by the 1p/19q codeletion and the more malignant glioblastomas (WHO grade IV astrocytomas) that can be diagnosed solely based on objective features on routine hematoxylin and eosin sections, no such objective criteria exist for the subclassification of grade II-III astrocytomas and oligoastrocytomas (A+OA II-III). In this study, we evaluated the prognostic and predictive value of the stem cell marker nestin in adult A+OA II-III (n=50) using immunohistochemistry and computer-assisted analysis on tissue microarrays. In addition, the correlation between nestin mRNA level and total survival was analyzed in the NCI Rembrandt database. The results showed that high nestin expression is a strong adverse prognostic factor for total survival (p=0.0004). The strength of the correlation was comparable to but independent of the isocitrate dehydrogenase 1/2 (IDH 1/2) mutation status. Histopathological grading and subclassification did not correlate significantly with outcome, although the interpretation of this finding is limited by the fact that grade III tumors were treated more aggressively than grade II tumors. These results suggest that nestin level and IDH 1/2 mutation status are strong prognostic features in A+OA II-III and possibly more helpful for treatment planning than routine histopathological variables such as oligodendroglial component (astrocytoma vs. oligoastrocytoma) and WHO grade (grade II vs. III). PMID:24519516

  19. High expression of the stem cell marker nestin is an adverse prognostic factor in WHO grade II-III astrocytomas and oligoastrocytomas.

    PubMed

    Hatanpaa, Kimmo J; Hu, Tianshen; Vemireddy, Vamsidhara; Foong, Chan; Raisanen, Jack M; Oliver, Dwight; Hiemenz, Matthew C; Burns, Dennis K; White, Charles L; Whitworth, L Anthony; Mickey, Bruce; Stegner, Martha; Habib, Amyn A; Fink, Karen; Maher, Elizabeth A; Bachoo, Robert M

    2014-03-01

    Infiltrating astrocytomas and oligoastrocytomas of low to anaplastic grade (WHO grades II and III), in spite of being associated with a wide range of clinical outcomes, can be difficult to subclassify and grade by the current histopathologic criteria. Unlike oligodendrogliomas and anaplastic oligodendrogliomas that can be identified by the 1p/19q codeletion and the more malignant glioblastomas (WHO grade IV astrocytomas) that can be diagnosed solely based on objective features on routine hematoxylin and eosin sections, no such objective criteria exist for the subclassification of grade II-III astrocytomas and oligoastrocytomas (A+OA II-III). In this study, we evaluated the prognostic and predictive value of the stem cell marker nestin in adult A+OA II-III (n = 50) using immunohistochemistry and computer-assisted analysis on tissue microarrays. In addition, the correlation between nestin mRNA level and total survival was analyzed in the NCI Rembrandt database. The results showed that high nestin expression is a strong adverse prognostic factor for total survival (p = 0.0004). The strength of the correlation was comparable to but independent of the isocitrate dehydrogenase 1/2 (IDH 1/2) mutation status. Histopathological grading and subclassification did not correlate significantly with outcome, although the interpretation of this finding is limited by the fact that grade III tumors were treated more aggressively than grade II tumors. These results suggest that nestin level and IDH 1/2 mutation status are strong prognostic features in A+OA II-III and possibly more helpful for treatment planning than routine histopathological variables such as oligodendroglial component (astrocytoma vs. oligoastrocytoma) and WHO grade (grade II vs. III).

  20. Changes in the BDNF-immunopositive cell population of neocortical layers I and II/III after focal cerebral ischemia in rats.

    PubMed

    Choi, Yongwon; Kang, Sung Goo; Kam, Kyung-Yoon

    2015-04-24

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely distributed in the central nervous system, including the cerebral cortex. BDNF plays an important role in normal neural development, survival of existing neurons, and activity-dependent neuroplasticity. BDNF can also be neuroprotective and evoke neurogenesis in certain pathological conditions, such as cerebral ischemia. Neocortical layer I is an important region that can integrate feedforward and feedback information from other cortical areas and subcortical regions. In addition, it has recently been proposed as a possible source of neuronal progenitor cells after ischemia. Therefore, we investigated changes in the BDNF-immunoreactive cell population of neocortical layers I and II/III after middle cerebral artery occlusion (MCAO)-induced cerebral ischemia in rats. In unaffected condition, the number of BDNF(+) cells in layer I was significantly less than in layer II/III in the cingulate cortex and in the motor and sensory areas. The increase in the number of BDNF(+) cells in layer I 8 days after MCAO was more remarkable than layer II/III, in all regions except the area of cingulate cortex farthest from the infarct core. Only BDNF(+)-Ox-42(+) cells showed a tendency to increase consistently toward the infarct core in both layers I and II/III, implying a major source of BDNF for response to ischemic injury. The present study suggests that some beneficial effects during recovery from ischemic injury, such as increased supportive microglia/macrophages, occur owing to a sensitive response of BDNF in layer I.

  1. Clinical significance of platelet-derived growth factor receptor-β gene expression in stage II/III gastric cancer with S-1 adjuvant chemotherapy

    PubMed Central

    Higuchi, Akio; Oshima, Takashi; Yoshihara, Kazue; Sakamaki, Kentaro; Aoyama, Toru; Suganuma, Nobuyasu; Yamamoto, Naoto; Sato, Tsutomu; Cho, Haruhiko; Shiozawa, Manabu; Yoshikawa, Takaki; Rino, Yasushi; Kunisaki, Chikara; Imada, Toshio; Masuda, Munetaka

    2017-01-01

    Overall survival remains unsatisfactory in stage II/III gastric cancer, even after curative surgery and adjuvant chemotherapy. Platelet-derived growth factor receptor-β (PDGFR-β) is associated with the proliferation of cancer cells. The present study therefore investigated the association of PDGFR-β gene expression with patient outcome in 134 stage II/III gastric cancer patients who received adjuvant chemotherapy with S-1. Relative PDGFR-β gene expression was measured in surgical cancer tissue and adjacent normal mucosa specimens by reverse transcription-quantitative polymerase chain reaction. The PDGFR-β gene expression levels were found to be significantly higher in the cancer tissues compared with the adjacent normal mucosa. A high level of PDGFR-β gene expression was associated with a significantly poorer 5-year overall survival rate compared with a low level of PDGFR-β expression. Upon multivariate analysis, PDGFR-β gene expression was found to be an independent predictor of survival. Overall, the study indicates that PDGFR-β overexpression in gastric cancer tissues is a useful independent predictor of outcome in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1.

  2. Image analysis-derived metrics of histomorphological complexity predicts prognosis and treatment response in stage II-III colon cancer

    PubMed Central

    Mezheyeuski, Artur; Hrynchyk, Ina; Karlberg, Mia; Portyanko, Anna; Egevad, Lars; Ragnhammar, Peter; Edler, David; Glimelius, Bengt; Östman, Arne

    2016-01-01

    The complexity of tumor histomorphology reflects underlying tumor biology impacting on natural course and response to treatment. This study presents a method of computer-aided analysis of tissue sections, relying on multifractal (MF) analyses, of cytokeratin-stained tumor sections which quantitatively evaluates of the morphological complexity of the tumor-stroma interface. This approach was applied to colon cancer collection, from an adjuvant treatment randomized study. Metrics obtained with the method acted as independent markers for natural course of the disease, and for benefit of adjuvant treatment. Comparative analyses demonstrated that MF metrics out-performed standard histomorphological features such as tumor grade, budding and configuration of invasive front. Notably, the MF analyses-derived “αmax” –metric constitutes the first response-predictive biomarker in stage II-III colon cancer showing significant interactions with treatment in analyses using a randomized trial-derived study population. Based on these results the method appears as an attractive and easy-to-implement tool for biomarker identification. PMID:27805003

  3. Equatorial π-stacking interactions in diruthenium (II,III) tetracarboxylate complexes containing extended π-systems

    NASA Astrophysics Data System (ADS)

    O'Rourke, Natasha F.; Ronaldson, Michael; Stanley Cameron, T.; Wang, Ruiyao; Aquino, Manuel A. S.

    2013-11-01

    The synthesis of three new valent-averaged tetracarboxylatodiruthenium (II,III) complexes, [Ru2(1-naphthylacetate)4(H2O)2](PF6)ṡ4THF, 1ṡ4THF, [Ru2(2-naphthoate)4(THF)2](PF6)ṡ3THF, 2ṡ3THF, and [Ru2(coumarin-3-carboxylate)4(MeOH)2](PF6)ṡMeOHṡH2O, 3ṡMeOHṡH2O, was accomplished using a well documented carboxylate exchange reaction. All three complexes were thoroughly characterized using infrared and UV-Vis spectroscopies, elemental analysis and X-ray diffraction. Due to the extended π-systems present, two of the complexes, 2ṡ3THF and 3ṡMeOHṡH2O, display extensive π-stacking in two dimensions, with similar interactions notably absent in 1ṡ4THF due to the perpendicular orientation of the naphthyl rings. Modest H-bonding is seen in complexes 1ṡ4THF and 3ṡMeOHṡH2O. As these types of complexes are noted secondary building units (SBU's) in the construction of metal-organic frameworks (MOF's), the significance of these interactions in stabilizing even larger, supramolecular structures, are noted.

  4. Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing.

    PubMed

    Rodríguez-Tornos, Fernanda M; Briz, Carlos G; Weiss, Linnea A; Sebastián-Serrano, Alvaro; Ares, Saúl; Navarrete, Marta; Frangeul, Laura; Galazo, Maria; Jabaudon, Denis; Esteban, José A; Nieto, Marta

    2016-02-03

    Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activity-dependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex.

  5. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

    PubMed

    Yamaue, Hiroki; Tsunoda, Takuya; Tani, Masaji; Miyazawa, Motoki; Yamao, Kenji; Mizuno, Nobumasa; Okusaka, Takuji; Ueno, Hideki; Boku, Narikazu; Fukutomi, Akira; Ishii, Hiroshi; Ohkawa, Shinichi; Furukawa, Masayuki; Maguchi, Hiroyuki; Ikeda, Masafumi; Togashi, Yosuke; Nishio, Kazuto; Ohashi, Yasuo

    2015-07-01

    Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

  6. Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: Do we have indications for individual risk stratification?

    PubMed Central

    2010-01-01

    Background Response to preoperative radiochemotherapy (RCT) in patients with locally advanced rectal cancer is very heterogeneous. Pathologic complete response (pCR) is accompanied by a favorable outcome. However, most patients show incomplete response. The aim of this investigation was to find indications for risk stratification in the group of intermediate responders to RCT. Methods From a prospective database of 496 patients with rectal adenocarcinoma, 107 patients with stage II/III cancers and intermediate response to preoperative 5-FU based RCT (ypT2/3 and TRG 2/3), treated within the German Rectal Cancer Trials were studied. Surgical treatment comprised curative (R0) total mesorectal excision (TME) in all cases. In 95 patients available for statistical analyses, residual transmural infiltration of the mesorectal compartment, nodal involvement and histolologic tumor grading were investigated for their prognostic impact on disease-free (DFS) and overall survival (OS). Results Residual tumor transgression into the mesorectal compartment (ypT3) did not influence DFS and OS rates (p = 0.619, p = 0.602, respectively). Nodal involvement after preoperative RCT (ypN1/2) turned out to be a valid prognostic factor with decreased DFS and OS (p = 0.0463, p = 0.0236, respectively). Persistent tumor infiltration of the mesorectum (ypT3) and histologic tumor grading of residual tumor cell clusters were strongly correlated with lymph node metastases after neoadjuvant treatment (p < 0.001). Conclusions Advanced transmural tumor invasion after RCT does not affect prognosis when curative (R0) resection is achievable. Residual nodal status is the most important predictor of individual outcome in intermediate responders to preoperative RCT. Furthermore, ypT stage and tumor grading turn out to be additional auxiliary factors. Future clinical trials for risk-adapted adjuvant therapy should be based on a synopsis of clinicopathologic parameters. PMID:20388220

  7. Voluntary exercise partially reverses neonatal alcohol-induced deficits in mPFC layer II/III dendritic morphology of male adolescent rats.

    PubMed

    Hamilton, G F; Criss, K J; Klintsova, A Y

    2015-08-01

    Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as fetal alcohol spectrum disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26- to 30-day-old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25 g kg(-1) day(-1)) on postnatal days (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC.

  8. Predicting Individualized Postoperative Survival for Stage II/III Colon Cancer Using a Mobile Application Derived from the National Cancer Data Base

    PubMed Central

    Gabriel, Emmanuel; Attwood, Kristopher; Thirunavukarasu, Pragatheeshwar; Al-Sukhni, Eisar; Boland, Patrick; Nurkin, Steven

    2017-01-01

    BACKGROUND Prediction calculators estimate postoperative survival and assist the decision-making process for adjuvant treatment. The objective of this study was to create a postoperative overall survival (OS) calculator for patients with stage II/III colon cancer. Factors that influence OS, including comorbidity and postoperative variables, were included. STUDY DESIGN The National Cancer Data Base was queried for patients with stage II/III colon cancer, diagnosed between 2004 and 2006, who had surgical resection. Patients were randomly divided to a testing (nt) cohort comprising 80% of the dataset and a validation (nv) cohort comprising 20%. Multivariable Cox proportional hazards regression of nt was performed to identify factors associated with 5-year OS. These were used to build a prediction model. The performance was assessed using the nv cohort and translated into mobile software. RESULTS A total of 129,040 patients had surgery. After exclusion of patients with carcinoma in situ, non-adenocarcinoma histology, more than 1 malignancy, stage I or IV disease, or missing data, 34,176 patients were used in the development of the calculator. Independent predictors of OS included patient-specific characteristics, pathologic factors, and treatment options, including type of surgery and adjuvant therapy. Length of postoperative stay and unplanned readmission rates were also incorporated as surrogates for postoperative complications (1-day increase in postoperative stay, hazard ratio [HR] 1.019, 95% CI 1.018 to 1.021, p < 0.001; unplanned readmission vs no readmission HR 1.35, 95% CI 1.25 to 1.45, p < 0.001). Predicted and actual 5-year OS rates were compared in the nv cohort with 5-year area under the curve of 0.77. CONCLUSIONS An individualized, postoperative OS calculator application was developed for patients with stage II/III colon cancer. This prediction model uses nationwide data, culminating in a highly comprehensive, clinically useful tool. PMID:26922599

  9. Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

    SciTech Connect

    Kato, Ken; Muro, Kei; Minashi, Keiko; Ohtsu, Atsushi; Ishikura, Satoshi; Boku, Narikazu; Takiuchi, Hiroya; Komatsu, Yoshito; Miyata, Yoshinori; Fukuda, Haruhiko

    2011-11-01

    Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

  10. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas.

    PubMed

    Olar, Adriana; Wani, Khalida M; Alfaro-Munoz, Kristin D; Heathcock, Lindsey E; van Thuijl, Hinke F; Gilbert, Mark R; Armstrong, Terri S; Sulman, Erik P; Cahill, Daniel P; Vera-Bolanos, Elizabeth; Yuan, Ying; Reijneveld, Jaap C; Ylstra, Bauke; Wesseling, Pieter; Aldape, Kenneth D

    2015-04-01

    Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities.

  11. Thyroid Function in Women after Multimodal Treatment for Breast Cancer Stage II/III: Comparison With Controls From a Population Sample

    SciTech Connect

    Reinertsen, Kristin Valborg; Cvancarova, Milada; Wist, Erik; Bjoro, Trine; Dahl, Alv A.; Danielsen, Turi; Fossa, Sophie D.

    2009-11-01

    Purpose: A possible association between thyroid diseases (TD) and breast cancer (BC) has been debated. We examined prevalence and development of TD in women after multimodal treatment for Stage II/III BC compared with women from a general population. Secondarily, we explored the impact of two different radiotherapy (RT) techniques (standardized field arrangements vs. computed tomography [CT]-based dose planning) on TD in BC patients examined 35-120 months after primary BC treatment. Methods and Materials: A total of 403 BC patients completed a questionnaire about TD and had blood samples taken for analyses of thyroid function. All had undergone postoperative RT with or without (2%) adjuvant systemic treatment. The results in the BC patients were compared with a cancer-free, age-matched control group from a general population (CGr). Results: There was higher prevalence of self-reported hypothyroidism in the BC patients as compared with the CGr (18% vs. 6%, p < 0.001). The raised prevalence was predominantly due to a substantial increase in the development of hypothyroidism after BC diagnosis, whereas the prevalence of hypothyroidism before BC diagnosis was similar to that observed in the CGr. Patients treated with CT-based RT showed a trend for increased post-BC development of hypothyroidism as compared with those treated with standardized field arrangements (p = 0.08). Conclusions: Hypothyroidism is significantly increased in women after multimodal treatment for Stage II/III BC. Radiation to the thyroid gland may be a contributing factor. BC patients should be routinely screened for hypothyroidism.

  12. Predictors of Long-Term Quality of Life for Survivors of Stage II/III Rectal Cancer in the Cancer Care Outcomes Research and Surveillance Consortium

    PubMed Central

    Charlton, Mary E.; Stitzenberg, Karyn B.; Lin, Chi; Schlichting, Jennifer A.; Halfdanarson, Thorvardur R.; Juarez, Grelda Yazmin; Pendergast, Jane F.; Chrischilles, Elizabeth A.; Wallace, Robert B.

    2015-01-01

    Purpose: Many patients do not receive guideline-recommended neoadjuvant chemoradiotherapy for resectable rectal cancer. Little is known regarding long-term quality of life (QOL) associated with various treatment approaches. Our objective was to determine patient characteristics and subsequent QOL associated with treatment approach. Methods: Our study was a geographically diverse population- and health system–based cohort study that included adults age 21 years or older with newly diagnosed stage II/III rectal cancer who were recruited from 2003 to 2005. Eligible patients were contacted 1 to 4 months after diagnosis and asked to participate in a telephone survey and to consent to medical record review, with separate follow-up QOL surveys conducted 1 and 7 years after diagnosis. Results: Two hundred thirty-nine patients with stage II/III rectal cancer were included in this analysis. Younger age (< 65 v ≥ 65 years: odds ratio, 2.49; 95% CI, 1.33 to 4.65) was significantly associated with increased odds of receiving neoadjuvant or adjuvant chemoradiotherapy. The adjuvant chemoradiotherapy group had significantly worse mean EuroQol-5D (range, 0 to 1) and Short Form-12 physical health component scores (standardized mean, 50) at 1-year follow-up than the neoadjuvant chemoradiotherapy group (0.75 v 0.85; P = .002; 37.2 v 43.3; P = .01, respectively) and the group that received only one or neither form of treatment (0.75 v 0.85; P = .02; 37.2 v 45.1; P = .008, respectively). Conclusion: Neoadjuvant treatment may result in better QOL and functional status 1 year after diagnosis. Further evaluation of patient and provider reasons for not pursuing neoadjuvant therapy is necessary to determine how and where to target process improvement and/or education efforts to ensure that patients have access to recommended treatment options. PMID:26080831

  13. The random-coil 'C' fragment of the dihydropyridine receptor II-III loop can activate or inhibit native skeletal ryanodine receptors.

    PubMed Central

    Haarmann, Claudia S; Green, Daniel; Casarotto, Marco G; Laver, Derek R; Dulhunty, Angela F

    2003-01-01

    The actions of peptide C, corresponding to (724)Glu-Pro(760) of the II-III loop of the skeletal dihydropyridine receptor, on ryanodine receptor (RyR) channels incorporated into lipid bilayers with the native sarcoplasmic reticulum membrane show that the peptide is a high-affinity activator of native skeletal RyRs at cytoplasmic concentrations of 100 nM-10 microM. In addition, we found that peptide C inhibits RyRs in a voltage-independent manner when added for longer times or at higher concentrations (up to 150 microM). Peptide C had a random-coil structure indicating that it briefly assumes a variety of structures, some of which might activate and others which might inhibit RyRs. The results suggest that RyR activation and inhibition by peptide C arise from independent stochastic processes. A rate constant of 7.5 x 10(5) s(-1).M(-1) was obtained for activation and a lower estimate for the rate constant for inhibition of 5.9 x 10(3) s(-1).M(-1). The combined actions of peptide C and peptide A (II-III loop sequence (671)Thr-Leu(690)) showed that peptide C prevented activation but not blockage of RyRs by peptide A. We suggest that the effects of peptide C indicate functional interactions between a part of the dihydropyridine receptor and the RyR. These interactions could reflect either dynamic changes that occur during excitation-contraction coupling or interactions between the proteins at rest. PMID:12620094

  14. FKBP12 modulation of the binding of the skeletal ryanodine receptor onto the II-III loop of the dihydropyridine receptor.

    PubMed Central

    O'Reilly, Fiona M; Robert, Mylène; Jona, Istvan; Szegedi, Csaba; Albrieux, Mireille; Geib, Sandrine; De Waard, Michel; Villaz, Michel; Ronjat, Michel

    2002-01-01

    In skeletal muscle, excitation-contraction coupling involves a functional interaction between the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR). The domain corresponding to Thr(671)-Leu(690) of the II-III loop of the skeletal DHPR alpha(1)-subunit is able to regulate RyR properties and calcium release from sarcoplasmic reticulum, whereas the domain corresponding to Glu(724)-Pro(760) antagonizes this effect. Two peptides, covering these sequences (peptide A(Sk) and C(Sk), respectively) were immobilized on polystyrene beads. We demonstrate that peptide A(Sk) binds to the skeletal isoform of RyR (RyR1) whereas peptide C(Sk) does not. Using surface plasmon resonance detection, we show that 1) domain Thr(671)-Leu(690) is the only sequence of the II-III loop binding with RyR1 and 2) the interaction of peptide A(Sk) with RyR1 is not modulated by Ca(2+) (pCa 9-2) nor by Mg(2+) (up to 10 mM). In contrast, this interaction is strongly potentiated by the immunophilin FKBP12 (EC(50) = 10 nM) and inhibited by both rapamycin (IC(50) = 5 nM) and FK506. Peptide A(Sk) induces a 300% increase of the opening probability of the RyR1 incorporated in lipid bilayer. Removal of FKBP12 from RyR1 completely abolishes this effect of domain A(Sk) on RyR1 channel behavior. These results demonstrate a direct interaction of the RyR1 with the discrete domain of skeletal DHPR alpha(1)-subunit corresponding to Thr(671)-Leu(690) and show that the association of FKBP12 with RyR1 specifically modulates this interaction. PMID:11751303

  15. The role of postmastectomy radiotherapy in clinically node-positive, stage II-III breast cancer patients with pathological negative nodes after neoadjuvant chemotherapy: an analysis from the NCDB

    PubMed Central

    Jiang, Shuai; Jiang, Wen; Chen, Kai; Kim, Betty Y.S.; Liu, Qiang; Jacobs, Lisa K.

    2016-01-01

    Purpose The role of postmastectomy radiotherapy (PMRT) in clinically node-positive, stage II-III breast cancer patients with pathological negative nodes (ypN0) after neoadjuvant chemotherapy (NAC) remains controversial. Methods A total of 1560 clinically node-positive, stage II-III breast cancer patients treated with NAC and mastectomy who achieved ypN0 between 1998 and 2009 in the National Cancer Database were analyzed. The effects of PMRT on overall survival (OS) for the entire cohort and multiple subgroups were evaluated. Imputation and propensity score matching were used as sensitivity analyses to minimize biases. Results Of the entire 1560 eligible patients, 903 (57.9%) received PMRT and 657 (42.1%) didn’t. At a median follow-up of 56.0 months, no statistical difference was observed for OS between two groups by univariate and multivariate analyses (P = 0.120; HR 1.571, 95% CI 0.839-2.943). On subgroup analyses, PMRT significantly improved OS in patients with clinical stage IIIB/IIIC disease, T3/T4 tumor, or residual invasive breast cancer after NAC (P < 0.05). This improvement in OS remained significant after sensitivity analyses for the propensity score-matched patients. Conclusions This study demonstrated that PMRT showed a heterogeneous effect in clinically node-positive, stage II-III breast cancer patients with ypN0 following NAC. PMRT improved OS for patients with clinical stage IIIB/IIIC disease, T3/T4 tumor, or residual invasive breast tumor after NAC. In the absence of definitive conclusions from prospective studies, including the ongoing NSABP B-51 trial, our findings may help identify specific groups of women with clinically node-positive, stage II-III breast cancers who could benefit from PMRT after NAC. PMID:26709538

  16. Effect of Postmastectomy Radiotherapy in Patients <35 Years Old With Stage II-III Breast Cancer Treated With Doxorubicin-Based Neoadjuvant Chemotherapy and Mastectomy

    SciTech Connect

    Garg, Amit K.; Oh, Julia L. Oswald, Mary Jane; Huang, Eugene; Strom, Eric A.; Perkins, George H.; Woodward, Wendy A.; Yu, T. Kuan; Tereffe, Welela; Meric-Bernstam, Funda; Hahn, Karin; Buchholz, Thomas A.

    2007-12-01

    Purpose: Postmastectomy radiotherapy (PMRT) improves locoregional control (LRC) in patients with high-risk features after mastectomy. Young age continues to evolve as a potentially important risk factor. The objective of this study was to assess the benefits of PMRT in patients <35 years old treated with doxorubicin-based neoadjuvant chemotherapy for Stage II-III breast cancer. Patients and Methods: We retrospectively analyzed 107 consecutive breast cancer patients <35 years old with Stage IIA-IIIC disease treated at our institution with doxorubicin-based neoadjuvant chemotherapy and mastectomy, with or without PMRT. The treatment groups were compared in terms of LRC and overall survival. Results: Despite more advanced disease stages, the patients who received PMRT (n = 80) had greater rates of LRC (5-year rate, 88% vs. 63%, p = 0.001) and better overall survival (5-year rate, 67% vs. 48%, p = 0.03) than patients who did not receive PMRT (n = 27). Conclusion: Among breast cancer patients <35 years old at diagnosis, the use of PMRT after doxorubicin-based neoadjuvant chemotherapy and mastectomy led to a statistically greater rate of LRC and overall survival compared with patients without PMRT. The benefit seen for PMRT in young patients provides valuable data to better tailor adjuvant, age-specific treatment decisions after mastectomy.

  17. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  18. Beating the Odds: Successful Establishment of a Phase II/III Clinical Research Trial in Resource-Poor Liberia during the Largest-Ever Ebola Outbreak

    PubMed Central

    Doe-Anderson, J; Baseler, B; Driscoll, P; Johnson, M; Lysander, J; McNay, L; Njoh, WS; Smolskis, M; Wehrlen, L; Zuckerman, J

    2016-01-01

    It has been argued that a country such as Liberia, not fully recovered from the devastation of decades of civil unrest, lacked the appropriate ethical and regulatory framework, basic human and health care services, and infrastructure to carry out clinical trials according to international standards of quality during a public health emergency. However, as Liberia, Sierra Leone, and Guinea were being ravaged by the largest and most devastating Ebola Virus Disease (EVD) outbreak ever recorded, the topic of conducting clinical trials of experimental vaccine and treatment candidates in these resource-poor countries generated the keen interest and concern of scientists, researchers, physicians, bioethicists, philanthropists, and even politicians. Decisive action on behalf of the Liberian government, and a timely positive and supportive response from the United States (U.S.) government, led to the formation of PREVAIL (Partnership for Research on Ebola Vaccines in Liberia) – a clinical research partnership between the two governments. Within a span of 12 weeks, this partnership accomplished the unimaginable: the successful initiation of a Phase II/III vaccine clinical trial for EVD in Liberia. This paper will discuss the dynamics of the research collaboration, barriers encountered, breakthroughs realized, key elements of success, and lessons learned in the process. PMID:28042619

  19. Ion paired chromatography of iron (II,III), nickel (II) and copper (II) as their 4,7-Diphenyl-1,10-phenanthroline chelates.

    PubMed

    Mudasir; Yoshioka, N; Inoue, H

    1997-07-01

    A reversed phase ion-paired chromatographic method that can be used to determine trace amounts of iron (II,III), nickel (II) and copper (II) was developed and applied to the determination of iron (II) and iron (III) levels in natural water. The separation of these metal ions as their 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline) chelates on an Inertsil ODS column was investigated by using acetonitrile-water (80/20, v/v) containing 0.06 M perchloric acid as mobile phase and diode array spectrophotometric detection at 250-650 nm. Chromatographic parameters such as composition of mobile phase and concentration of perchloric acid in mobile phase were optimized. The calibration graphs of iron (II), nickel (II) and copper (II) ions were linear (r > 0.991) in the concentration range 0-0.5, 0-2.0 and 0-4.0 mug ml(-1), respectively. The detection limit of iron (II), nickel (II) and copper (II) were 2.67, 5.42 and 18.2 ng ml(-1) with relative standard deviation (n = 5) of 3.11, 5.81 and 7.16% at a concentration level of 10 ng ml(-1) for iron (II) and nickel (II) and 25 ng ml(-1) for copper (II), respectively. The proposed method was applied to the determination of iron(II) and iron(III) in tap water and sea water samples without any interference from other common metal ions.

  20. Rab27a GTPase modulates L-type Ca2+ channel function via interaction with the II-III linker of CaV1.3 subunit.

    PubMed

    Reichhart, Nadine; Markowski, Magdalena; Ishiyama, Shimpei; Wagner, Andrea; Crespo-Garcia, Sergio; Schorb, Talitha; Ramalho, José S; Milenkovic, Vladimir M; Föckler, Renate; Seabra, Miguel C; Strauß, Olaf

    2015-11-01

    In a variety of cells, secretory processes require the activation of both Rab27a and L-type channels of the Ca(V)1.3 subtype. In the retinal pigment epithelium (RPE), Rab27a and Ca(V)1.3 channels regulate growth-factor secretion towards its basolateral side. Analysis of murine retina sections revealed a co-localization of both Rab27a and Ca(V)1.3 at the basolateral membrane of the RPE. Heterologously expressed Ca(V)1.3/β3/α2δ1 channels showed negatively shifted voltage-dependence and decreased current density of about 70% when co-expressed with Rab27a. However, co-localization analysis using α(5)β(1) integrin as a membrane marker revealed that Rab27a co-expression reduced the surface expression of Ca(V)1.3 only about 10%. Physical binding of heterologously expressed Rab27a with Ca(V)1.3 channels was shown by co-localization in immunocytochemistry as well as co-immunoprecipitation which was abolished after deletion of a MyRIP-homologous amino acid sequence at the II-III linker of the Ca(V)1.3 subunit. Rab27a over-expression in ARPE-19 cells positively shifted the voltage dependence, decreased current density of endogenous Ca(V)1.3 channels and reduced VEGF-A secretion. We show the first evidence of a direct functional modulation of an ion channel by Rab27a suggesting a new mechanism of Rab and ion channel interaction in the control of VEGF-A secretion in the RPE.

  1. Mastectomy With Immediate Expander-Implant Reconstruction, Adjuvant Chemotherapy, and Radiation for Stage II-III Breast Cancer: Treatment Intervals and Clinical Outcomes

    SciTech Connect

    Wright, Jean L.; Cordeiro, Peter G.; Ben-Porat, Leah; Van Zee, Kimberly J.; Hudis, Clifford; Beal, Kathryn; McCormick, Beryl

    2008-01-01

    Purpose: To determine intervals between surgery and adjuvant chemotherapy and radiation in patients treated with mastectomy with immediate expander-implant reconstruction, and to evaluate locoregional and distant control and overall survival in these patients. Methods and Materials: Between May 1996 and March 2004, 104 patients with Stage II-III breast cancer were routinely treated at our institution under the following algorithm: (1) definitive mastectomy with axillary lymph node dissection and immediate tissue expander placement, (2) tissue expansion during chemotherapy, (3) exchange of tissue expander for permanent implant, (4) radiation. Patient, disease, and treatment characteristics and clinical outcomes were retrospectively evaluated. Results: Median age was 45 years. Twenty-six percent of patients were Stage II and 74% Stage III. All received adjuvant chemotherapy. Estrogen receptor staining was positive in 77%, and 78% received hormone therapy. Radiation was delivered to the chest wall with daily 0.5-cm bolus and to the supraclavicular fossa. Median dose was 5040 cGy. Median interval from surgery to chemotherapy was 5 weeks, from completion of chemotherapy to exchange 4 weeks, and from exchange to radiation 4 weeks. Median interval from completion of chemotherapy to start of radiation was 8 weeks. Median follow-up was 64 months from date of mastectomy. The 5-year rate for locoregional disease control was 100%, for distant metastasis-free survival 90%, and for overall survival 96%. Conclusions: Mastectomy with immediate expander-implant reconstruction, adjuvant chemotherapy, and radiation results in a median interval of 8 weeks from completion of chemotherapy to initiation of radiation and seems to be associated with acceptable 5-year locoregional control, distant metastasis-free survival, and overall survival.

  2. Fibroblast Growth Factor 2-A Predictor of Outcome for Patients Irradiated for Stage II-III Non-Small-Cell Lung Cancer

    SciTech Connect

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2012-01-01

    Purpose: The prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients with non-small-cell lung cancer (NSCLC) is unclear. The present study investigated the effect of tumor cell expression of FGF-2 on the outcome of 60 patients irradiated for Stage II-III NSCLC. Methods and Materials: The effect of FGF-2 expression and 13 additional factors on locoregional control (LRC), metastasis-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These additional factors included age, gender, Karnofsky performance status, histologic type, histologic grade, T and N category, American Joint Committee on Cancer stage, surgery, chemotherapy, pack-years, smoking during radiotherapy, and hemoglobin during radiotherapy. Locoregional failure was identified by endoscopy or computed tomography. Univariate analyses were performed with the Kaplan-Meier method and the Wilcoxon test and multivariate analyses with the Cox proportional hazard model. Results: On univariate analysis, improved LRC was associated with surgery (p = .017), greater hemoglobin levels (p = .036), and FGF-2 negativity (p <.001). On multivariate analysis of LRC, surgery (relative risk [RR], 2.44; p = .037), and FGF-2 expression (RR, 5.06; p <.001) maintained significance. On univariate analysis, improved MFS was associated with squamous cell carcinoma (p = .020), greater hemoglobin levels (p = .007), and FGF-2 negativity (p = .001). On multivariate analysis of MFS, the hemoglobin levels (RR, 2.65; p = .019) and FGF-2 expression (RR, 3.05; p = .004) were significant. On univariate analysis, improved OS was associated with a lower N category (p = .048), greater hemoglobin levels (p <.001), and FGF-2 negativity (p <.001). On multivariate analysis of OS, greater hemoglobin levels (RR, 4.62; p = .002) and FGF-2 expression (RR, 3.25; p = .002) maintained significance. Conclusions: Tumor cell expression of FGF-2 appeared to be an independent negative predictor

  3. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

    PubMed Central

    Bogdanik, Laurent P.; Osborne, Melissa A.; Davis, Crystal; Martin, Whitney P.; Austin, Andrew; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen M.

    2015-01-01

    Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system. PMID:26460027

  4. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

    PubMed

    Dierks, Thomas; Schlotawa, Lars; Frese, Marc-André; Radhakrishnan, Karthikeyan; von Figura, Kurt; Schmidt, Bernhard

    2009-04-01

    Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been

  5. Docetaxel, cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stage II/III N1, 2 esophageal cancer.

    PubMed

    Hashiguchi, Tadasuke; Nasu, Motomi; Hashimoto, Takashi; Kuniyasu, Tetsuji; Inoue, Hirohumi; Sakai, Noritaka; Ouchi, Kazutomo; Amano, Takayuki; Isayama, Fuyumi; Tomita, Natsumi; Iwanuma, Yoshimi; Tsurumaru, Masahiko; Kajiyama, Yoshiaki

    2014-09-01

    To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and

  6. SU-E-J-88: Margin Reduction of Level II/III Planning Target Volume for Image-Guided Simultaneous Integrated Boost Head-And-Neck Treatment

    SciTech Connect

    Can, S; Neylon, J; Qi, S; Santhanam, A; Low, D

    2014-06-01

    Purpose: To investigate the feasibility of improved normal tissue sparing for head-and-neck (H'N) image-guided radiotherapy (IGRT) by employing tighter CTV-to-PTV margins for target level II/III though a GPU-based deformable image registration and dose accumulation framework. Methods: Ten H'N simultaneous integrated boost cases treated on TomoTherapy were retrospectively analyzed. Weekly kVCT scans in addition to daily MVCT scans were acquired for each patient. Reduced margin plans were generated with 0- mm margin for level II and III PTV (while 3-5 mm margin for PTV1) and compared with the standard margin plan using 3-5mm margin to all CTV1-3 (reference plan). An in-house developed GPU-based 3D image deformation tool was used to register and deform the weekly KVCTs with the planning CT and determine the delivered mean/minimum/maximum dose, dose volume histograms (DVHs), etc. Results: Compared with the reference plans, the averaged cord maximum, the right and left parotid doses reduced by 22.7 %, 16.5 %, and 9 % respectively in the reduced margin plans. The V95 for PTV2 and PTV3 were found within 2 and 5% between the reference and tighter margin plans. For the reduced margin plans, the averaged cumulative mean doses were consistent with the planned dose for PTV1, PTV2 and PTV3 within 1.5%, 1.7% and 1.4%. Similar dose variations of the delivered dose were seen for the reference and tighter margin plans. The delivered maximum and mean doses for the cord were 3.55 % and 2.37% higher than the planned doses; a 5 % higher cumulative mean dose for the parotids was also observed for the delivered dose than the planned doses in both plans. Conclusion: By imposing tighter CTV-to-PTV margins for level II and III targets for H'N irradiation, acceptable cumulative doses were achievable when coupled with weekly kVCT guidance while improving normal structure sparing.

  7. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/− cetuximab in oesophageal cancer

    PubMed Central

    Crosby, T; Hurt, C N; Falk, S; Gollins, S; Staffurth, J; Ray, R; Bridgewater, J A; Geh, J I; Cunningham, D; Blazeby, J; Roy, R; Maughan, T; Griffiths, G; Mukherjee, S

    2017-01-01

    Background: The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence. Methods: SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m−2 (day 1) and capecitabine 625 mg m−2 bd (days 1–21) for four cycles +/− cetuximab 400 mg m−2 day 1 then by 250 mg m−2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility. Results: About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9–48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7–42.3) in dCRT and 24.7 (18.6–31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93–1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3–29.9) and 15.9 (10.7–20.8) months, respectively (HR=1.28, 95% CIs: 0.94–1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS. Conclusions: The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy. PMID:28196063

  8. Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

    SciTech Connect

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2011-06-01

    Purpose: Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients. Methods and Materials: Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R. Results: On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p < 0.048), surgery (p < 0.042), no smoking during radiotherapy (p = 0.024), and no EPO expression (p = 0.001). A trend was observed for a KPS of >70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of {>=}12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of {>=}12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R. Conclusions: EPO expression of tumor cells

  9. Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

    PubMed

    Jain, Minish M; Gupte, Smita U; Patil, Shekhar G; Pathak, Anand B; Deshmukh, Chetan D; Bhatt, Niraj; Haritha, Chiramana; Govind Babu, K; Bondarde, Shailesh A; Digumarti, Raghunadharao; Bajpai, Jyoti; Kumar, Ravi; Bakshi, Ashish V; Bhattacharya, Gouri Sankar; Patil, Poonam; Subramanian, Sundaram; Vaid, Ashok K; Desai, Chirag J; Khopade, Ajay; Chimote, Geetanjali; Bapsy, Poonamalle P; Bhowmik, Shravanti

    2016-02-01

    Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2

  10. The Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)

    SciTech Connect

    Shim, Su Jung; Park, Won; Huh, Seung Jae; Choi, Doo Ho; Shin, Kyung Hwan; Lee, Nam Kwon; Suh, Chang-Ok; Keum, Ki Chang; Kim, Yong Bae; Ahn, Seung Do; Kim, Su Ssan; Ha, Sung W.; Chie, Eui Kyu; Kim, Kyubo; Shin, Hyun Soo; Kim, Jin Hee; Lee, Hyung-Sik

    2014-01-01

    Purpose: The purpose of this study was to investigate the role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) in clinical stage II-III breast cancer patients with pN0. Methods and Materials: We retrospectively identified 417 clinical stage II-III breast cancer patients who achieved an ypN0 at surgery after receiving NAC between 1998 and 2009. Of these, 151 patients underwent mastectomy after NAC. The effect of PMRT on disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and overall survival (OS) was evaluated by multivariate analysis including known prognostic factors using the Kaplan-Meier method and compared using the log–rank test and Cox proportional regression analysis. Results: Of the 151 patients who underwent mastectomy, 105 (69.5%) received PMRT and 46 patients (30.5%) did not. At a median follow-up of 59 months, 5 patients (3.3%) developed LRR (8 sites of recurrence) and 14 patients (9.3%) developed distant metastasis. The 5-year DFS, LRRFS, and OS rates were 91.2, 98.1, and 93.3% with PMRT and 83.0%, 92.3%, and 89.9% without PMRT, respectively (all P values not significant). By univariate analysis, only age (≤40 vs >40 years) was significantly associated with decreased DFS (P=.027). By multivariate analysis, age (≤40 vs >40 years) and pathologic T stage (0-is vs 1 vs 2-4) were significant prognostic factors affecting DFS (hazard ratio [HR] 0.353, 95% confidence interval [CI] 0.135-0.928, P=.035; HR 2.223, 95% CI 1.074-4.604, P=.031, respectively). PMRT showed no correlation with a difference in DFS, LRRFS, or OS by multivariate analysis. Conclusions: PMRT might not be necessary for pN0 patients after NAC, regardless of clinical stage. Prospective randomized clinical trial data are needed to assess whether PMRT can be safely omitted in pN0 patients after NAC and mastectomy for clinical stage II-III breast cancer.

  11. Randomized phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck: Japan Clinical Oncology Group Study (JCOG1008).

    PubMed

    Kunieda, Futoshi; Kiyota, Naomi; Tahara, Makoto; Kodaira, Takeshi; Hayashi, Ryuichi; Ishikura, Satoshi; Mizusawa, Junki; Nakamura, Kenichi; Fukuda, Haruhiko; Fujii, Masato

    2014-08-01

    A randomized Phase II/III study was launched in Japan to evaluate the non-inferiority of concurrent chemoradiotherapy with weekly cisplatin (40 mg/m(2)) compared with concurrent chemoradiotherapy with 3-weekly cisplatin (100 mg/m(2)) for post-operative high-risk patients with locally advanced squamous cell carcinoma of head and neck. This study began in October 2012, and a total of 260 patients will be accrued from 18 institutions within 5 years. The primary endpoint of the Phase II part is proportion of treatment completion and that of the Phase III part is overall survival. The secondary endpoints are relapse-free survival, local relapse-free survival, nutrition-support-free survival, non-hospitalized treatment period during permissible treatment period and adverse events. This trial was registered at the UMIN Clinical Trials Registry as UMIN 000009125 [http://www.umin.ac.jp/ctr/].

  12. A Phase II/III randomized controlled trial comparing perioperative versus postoperative chemotherapy with mFOLFOX6 for lower rectal cancer with suspected lateral pelvic node metastasis: Japan Clinical Oncology Group Study JCOG1310 (PRECIOUS study).

    PubMed

    Ohue, Masayuki; Iwasa, Satoru; Kanemitsu, Yukihide; Hamaguchi, Tetsuya; Shiozawa, Manabu; Ito, Masaaki; Yasui, Masayoshi; Katayama, Hiroshi; Mizusawa, Junki; Shimada, Yasuhiro

    2017-01-01

    A randomized phase II/III trial was started in May 2015 comparing perioperative versus postoperative chemotherapy with modified infusional fluorouracil and folinic acid with oxaliplatin for lower rectal cancer patients with suspected lateral pelvic node metastasis. The standard arm is total mesorectal excision or tumor-specific mesorectal excision with lateral pelvic node dissection (LND) followed by postoperative chemotherapy (modified infusional fluorouracil and folinic acid with oxaliplatin; 12 cycles). The experimental (perioperative chemotherapy) arm is six courses of modified infusional fluorouracil and folinic acid with oxaliplatin before and six courses after total mesorectal excision with lateral pelvic node dissection. The aim of this trial is to confirm the superiority of perioperative chemotherapy. A total of 330 patients will be enrolled over 7 years. The primary endpoint in Phase II part is proportion of R0 resection and that in Phase III part is overall survival. Secondary endpoints are progression-free survival, local progression-free survival, etc. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017603 [http://www.umin.ac.jp/ctr/index-j.htm].

  13. Expression and prognostic significance of APAF-1, caspase-8 and caspase-9 in stage II/III colon carcinoma: caspase-8 and caspase-9 is associated with poor prognosis.

    PubMed

    Sträter, Jörn; Herter, Ines; Merkel, Gaby; Hinz, Ulf; Weitz, Jürgen; Möller, Peter

    2010-08-15

    Apoptosis protease activating factor-1 (APAF-1), caspase-8 and caspase-9 are important factors in the execution of death signals. To study their prognostic influence in colon carcinoma, expression of APAF-1, caspase-8 and caspase-9 was determined by immunohistochemistry in normal colon mucosa (n = 8) and R0-resected stage II/III colon carcinomas (n >or= 124) using a semiquantitative score. Staining results were correlated with disease-free survival by Kaplan-Meier estimates, and multivariate Cox analyses were performed. In normal colon, APAF-1 and caspase-8 are most strongly expressed in the luminal surface epithelium, whereas caspase-9 is expressed all along the crypt axis. In colon carcinomas, there is considerable variability in the expression of these proapoptotic factors, although complete loss of caspase-8 and caspase-9 is rare. APAF-1 expression did not correlate with disease-free survival. Instead, both expression of caspase-9 and high-level expression of caspase-8 in a majority of tumor cells were significantly associated with adverse prognosis (p = 0.004 and p = 0.029, respectively). The influence of caspase-8 expression was mainly seen in patients with stage III colon carcinoma (p = 0.011), whereas the prognostic influence of caspase-9 expression was significant in stage II cases (p = 0.037) and just failed to be significant in stage III tumors (p = 0.0581). After adjusting for confounding factors in a multivariate Cox analysis, the effect of caspase-9 in predicting disease-free survival was confirmed (p = 0.003). Our data suggest that, in colon carcinomas, expression of caspase-8 and caspase-9 is significantly associated with poor survival. Caspase-9 may be an independent prognosticator in colon carcinoma.

  14. Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial

    PubMed Central

    Vahlquist, A; Blockhuys, S; Steijlen, P; van Rossem, K; Didona, B; Blanco, D; Traupe, H

    2014-01-01

    Summary Background Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. Objective To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. Methods This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Results Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. Conclusions The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis. PMID:24102348

  15. Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

    PubMed Central

    Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

    2011-01-01

    Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

  16. Long-term Survival Outcomes Following Internal Mammary Node Irradiation in Stage II-III Breast Cancer: Results of a Large Retrospective Study With 12-Year Follow-up

    SciTech Connect

    Chang, Jee Suk; Park, Won; Kim, Yong Bae; Lee, Ik Jae; Keum, Ki Chang; Lee, Chang Geol; Choi, Doo Ho; Suh, Chang-Ok; Huh, Seung Jae

    2013-08-01

    Purpose: To examine the effect of internal mammary node irradiation (IMNI) on disease-free survival (DFS) and overall survival (OS) in breast cancer patients treated with modified radical mastectomy and postoperative radiation therapy. Methods and Materials: Between 1994 and 2002, 396 patients with stage II-III breast cancer were treated with postmastectomy radiation therapy with (n=197) or without (n=199) IMNI. Patients who received neoadjuvant chemotherapy were excluded. IMNI was administered at the clinical discretion of the treating physician. Median RT dose was 50.4 Gy (range, 45.0-59.4 Gy) in 28 fractions, with inclusion of the supraclavicular fossa in 96% of patients. Adjuvant chemotherapy was administered to 99.7% of the patients and endocrine therapy to 53%. Results: The median follow-up was 149 months (range, 124-202). IMNI patients had more advanced nodal stage and non-high grade tumors than those without IMNI (P<.001). Otherwise, disease and treatment characteristics were well balanced. The 10-year DFS with and without IMNI was 65% and 57%, respectively (P=.05). Multivariate analysis demonstrated that IMNI was an independent, positive predictor of DFS (hazard ratio [HR], 0.70; P=.02). Benefits of IMNI in DFS were seen most apparently in N2 patients (HR, 0.44; 95% confidence interval [CI], 0.26-0.74) and inner/central tumors (HR, 0.55; 95% CI, 0.34-0.90). The 10-year OS with and without IMNI was 72% and 66%, respectively (P=.62). The 10-year DFS and OS were 61%, and 69%, respectively. Conclusions: Internal mammary node irradiation significantly improved DFS in postmastectomy breast cancer patients. Pending long-term results from randomized trials, treatment of internal mammary nodes should be considered in postmastectomy radiation therapy.

  17. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

    PubMed

    Coleman, R; Woodward, E; Brown, J; Cameron, D; Bell, R; Dodwell, D; Keane, M; Gil, M; Davies, C; Burkinshaw, R; Houston, S J; Grieve, R J; Barrett-Lee, P J; Thorpe, H

    2011-06-01

    The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

  18. Ozone loss rates in the Arctic winter stratosphere during 1994-2000 derived from POAM II/III and ILAS observations: Implications for relationships among ozone loss, PSC occurrence, and temperature

    NASA Astrophysics Data System (ADS)

    Terao, Yukio; Sugita, Takafumi; Sasano, Yasuhiro

    2012-03-01

    Quantitative chemical ozone loss rates at the 475 K isentropic surface inside the Arctic polar vortex are evaluated for six winters (January through March) using a satellite-based Match technique. Satellite observational data are taken from the Polar Ozone and Aerosol Measurement (POAM) II for 1994-1996, the Improved Limb Atmospheric Spectrometer (ILAS) for 1997, and the POAM III for 1999-2000. The largest ozone loss rates were observed in the end of January 1995 (˜50 ± 20 ppbv d-1), February 1996 (˜40-50 ± 15 ppbv d-1), February 1997 (˜40 ± 8 ppbv d-1), January 2000 (˜60 ± 30 ppbv d-1), and early March 2000 (˜40 ± 10 ppbv d-1). The probability of polar stratospheric cloud (PSC) existence is estimated using aerosol extinction coefficient data from POAM II/III and ILAS. Ozone loss and the PSC probability are strongly correlated and an absolute increase of 10% in the PSC probability is found to amplify the chemical ozone loss rate during Arctic winter by approximately 25 ± 6 ppbv per day or 3.2 ± 0.7 ppbv per sunlit hour. Relationships between average Arctic winter ozone loss rates and various PSC- and temperature-related indices are investigated, including the area of polar vortex that is colder than the threshold temperature for PSC existence (APSC), the PSC formation potential (PFP), and the potential for activation of chlorine (PACl). Of these three, PACl provides the best proxy representation of interannual variability in Arctic ozone loss at the 475 K level. Large ozone loss occurred primarily for air masses that experienced low temperatures between 187 K and 195 K within the previous 10 days and the ozone loss rates clearly increase with decreasing the minimum temperature. The particularly large ozone losses of ˜9 ± 3 ppbv per sunlit hour in February 1996 and January 2000 were associated with low minimum temperatures of 187-189 K, simultaneously with high PSC probabilities.

  19. Adult Education in Israel, II-III.

    ERIC Educational Resources Information Center

    Kirmayer, Paul, Ed.; Pinnes, Noy, Ed.

    This is the second booklet in English that deals with adult education in Israel. The following papers are included: "Editors' Notes" (Paul Kirmayer, Noy Pinnes); "Introduction" (Meir Peretz); "Defining 'Adult Education'" (Yehezkel Cohen); "Planning Study Programs for Adults" (Rachel Tokatli); "The Role…

  20. Evaluation of safety and immunogenicity of HNVAC, an MDCK-based H1N1 pandemic influenza vaccine, in Phase I single centre and Phase II/III multi-centre, double-blind, randomized, placebo-controlled, parallel assignment studies.

    PubMed

    Basavaraj, V H; Sampath, G; Hegde, Nagendra R; Mohan, V Krishna; Ella, Krishna M

    2014-07-31

    The clinical evaluation of the MDCK-based H1N1 pandemic influenza vaccine HNVAC in adults aged 18-65 years is reported. In the Phase I randomized, double-blind, placebo-controlled, single-centre study, 160 subjects were parallelly assigned 3:1 to vaccine:placebo groups (n=60:20) with both the aluminium hydroxide adjuvanted and non-adjuvanted vaccine formulations. A single dose of both the formulations containing 15 μg of haemagglutinin protein showed minimal adverse reactions, the most common of which were pain at injection site (11.67%) and fever (10.00%). Both formulations produced 74-81% seroprotection (SRP: titre of ≥40), 67-70% seroconversion (SRC: four-fold increase in titres between days 0 and 21), and a four-fold increase in geometric mean titres (GMT). Aluminium hydroxide did not have a significant effect either on immunogenicity or on reactogenicity. Nevertheless, based on its recognized positive effects on the stability and immunogenicity of many vaccines, and its marginal benefit in both pre-clinical and Phase I studies of HNVAC, alum adjuvanted HNVAC was further tested in a staggered Phase II/III randomized, double-blind, placebo-controlled, multi-centre study of 200 and 195 subjects, respectively, parallelly assigned 4:1 to adjuvanted vaccine and placebo groups. In these studies, the most common adverse reactions were pain at injection site (6.88% and 5.77% in Stage 1 and Stage 2, respectively) and fever (7.50% and 7.05%, respectively), and a single dose resulted in 87-90% SRP, 85-86% SRC, and a nearly six-fold increase in GMT, meeting or exceeding licensing criteria. It is concluded that HNVAC is safe and immunogenic to adults of 18-65 years.

  1. Play the winner for phase II/III clinical trials.

    PubMed

    Yao, Q; Wei, L J

    In comparing two treatments under a typical sequential clinical trial setting, a 50-50 randomization design generates reliable data for making efficient inferences about the treatment difference for the benefit of patients in the general population. However, if the treatment difference is large and the endpoint of the study is potentially fatal, it does not seem appropriate to sacrifice a large number of study patients who are assigned to the inferior arm. An adaptive design is a data-dependent treatment allocation rule that sequentially uses accumulating information about the treatment difference during the trial to modify the allocation rule for new study patients. In this article, we utilize real trials from AIDS and cancer to illustrate the advantage of using adaptive designs. Specifically we show that, with adaptive designs, the loss of power for testing the equality of two treatments is negligible. Moreover, the study patients do not have to pay a handsome price for the benefit of future patients. We also propose multi-stage adaptive rules to relax the administrative burden of implementing the study and to handle continuous response variables, such as the failure time in survival analysis.

  2. Alpha Trianguli Australis (K2 II-III) - Hybrid or composite?

    NASA Technical Reports Server (NTRS)

    Ayres, T. R.

    1985-01-01

    The prototype hybrid-spectrum giant Alpha Trianguli Australis exhibits a far-ultraviolet continuum which is considerably bluer than would be expected of a star of its optical colors, suggesting the presence of a previously unrecognized companion. If the K-type primary is as luminous as indicated by the widths of its Ca II and H-alpha lines, the companion could be an early F-type dwarf that only recently has arrived on the main sequence. Indeed, the flux of C IV from Alpha TrA - an important measure of hybridness - would not be inconsistent with that expected from a very young chromospherically active F star.

  3. Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

    SciTech Connect

    Fowble, Barbara L.; Einck, John P.; Kim, Danny N.; McCloskey, Susan; Mayadev, Jyoti; Yashar, Catheryn; Chen, Steven L.; Hwang, E. Shelley

    2012-06-01

    Purpose: To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). Methods and Materials: Seven breast cancer physicians from University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. Results: Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having {<=}10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. Conclusions: In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within University of California Athena Breast Health Network.

  4. Multipurpose Wetlands Phase II/III: final design and ongoing research investigations

    USGS Publications Warehouse

    Babbitt, Bruce; Beard, Daniel P.; Hancock, Lawrence F.

    1994-01-01

    The Eastern Municipal Water District (EMWD), the Bureau of Reclamation (USBR), and the National Biological Survey (NBS), in consultation with other governmental agencies, the academic community, and environmental groups, are involved in a cooperative wetlands research and demonstration effort. This report reflects progress through the first 3 years of a 5-year program. The goal of the Multipurpose Wetlands Research and Demonstration Project is to evaluate and expand the use of reclaimed water and contaminated ground water through the incorporation of multipurpose constructed wetlands into EMWD's total water resources management program. The focus of the wetlands is the development of design, construction, and operation criteria that will provide a cost-effective and innovative alternative for managing water resources and provide other public benefits in arid areas. The program also recognizes the fact that naturally-occurring wetlands, both coastal and inland, have been disappearing at an alarming rate.

  5. Low-metallicity Star Formation and Pop III-II Transition

    NASA Astrophysics Data System (ADS)

    Omukai, Kazuyuki

    2010-10-01

    The first stars in the universe were typically very massive, but those near us are not. The metallicity in the star-forming gas is thought to have played a key role in this transition of characteristic stellar mass scale. By studying the evolution of low-metallicity star-forming clouds up to the formation of protostars by way of radiation hydrodynamics with spherical symmetry, we discuss their fragmentation mass scales. The critical metallicity for low-mass fragmentation is in the range of Zcr = 10-6-10-5Zsolar. Although the exact value is still unknown due to uncertain dust nature in the early universe, the small value of Zcr means that low-mass star formation begun just after the first episode of metal enrichment. We also evaluate the upper limit on the stellar mass by the stellar feedback. Owing to the higher density in the envelope and thus higher protostellar accretion rate, the upper limit of stellar mass increases toward lower matallicity.

  6. Prognostic and predictive significance of MSI in stages II/III colon cancer.

    PubMed

    Saridaki, Zacharenia; Souglakos, John; Georgoulias, Vassilis

    2014-06-14

    In colon cancer, classic disease staging remains the key prognosis and treatment determinant. Although adjuvant chemotherapy has an established role in stage III colon cancer patients, in stage II it is still a subject of controversy due to its restriction to a small subgroup of patients with high-risk histopathologic features. Patients with stage II tumors form a highly heterogeneous group, with five-year relative overall survival rates ranging from 87.5% (IIA) to 58.4% (IIC). Identifying those for whom adjuvant chemotherapy would be appropriate and necessary has been challenging, and prognostic markers which could serve in the selection of patients more likely to recur or benefit from adjuvant chemotherapy are eagerly needed. The stronger candidate in this category seems to be microsatellite instability (MSI). The recently reported European Society for Medical Oncology guidelines suggest that MSI should be evaluated in stage II colorectal cancer patients in order to contribute in treatment decision-making regarding chemotherapy administration. The hypothetical predictive role of MSI regarding its response to 5-fluorouracil-based adjuvant chemotherapy has proven a much more difficult issue to address. Almost every possible relation between MSI and chemotherapy outcome has been described in the adjuvant colon cancer setting in the international literature, and the matter is far from being settled. In this current report we critically evaluate the prognostic and predictive impact of MSI status in patients with stage II and stage III colon cancer patients.

  7. Structure and function of the ESCRT II-III interface in multivesicular body biogenesis

    PubMed Central

    Im, Young Jun; Wollert, Thomas; Boura, Evzen; Hurley, James H.

    2009-01-01

    SUMMARY The ESCRT-II-ESCRT-III interaction coordinates the sorting of ubiquitinated cargo with the budding and scission of intralumenal vesicles into multivesicular bodies. The interacting regions of these complexes were mapped to the second winged-helix domain of human ESCRT-II subunit VPS25 and the first helix of ESCRT-III subunit VPS20. The crystal structure of this complex was determined at 2.0 Å resolution. Residues involved in structural interactions explain the specificity of ESCRT-II for Vps20, and are critical for cargo sorting in vivo. ESCRT-II directly activates ESCRT-III driven vesicle budding and scission in vitro via these structural interactions. VPS20 and ESCRT-II bind membranes with nanomolar affinity, explaining why binding to ESCRT-II is dispensable for the recruitment of Vps20 to membranes. Docking of the ESCRT-II -VPS202 supercomplex reveals a convex membrane-binding surface, suggesting a hypothesis for negative membrane curvature induction in the nascent intralumenal vesicle. PMID:19686684

  8. Microsatellite instability & survival in patients with stage II/III colorectal carcinoma

    PubMed Central

    Srdjan, Markovic; Jadranka, Antic; Ivan, Dimitrijevic; Branimir, Zogovic; Daniela, Bojic; Petar, Svorcan; Velimir, Markovic; Zoran, Krivokapic

    2016-01-01

    Background & objectives: The two key aspects associated with the microsatellite instability (MSI) as genetic phenomenon in colorectal cancer (CRC) are better survival prognosis, and the varying response to 5-fluorouracil (5-FU)-based chemotherapy. This study was undertaken to measure the survival of surgically treated patients with stages II and III CRC based on the MSI status, the postoperative 5-FU treatment as well as clinical and histological data. Methods: A total of 125 consecutive patients with stages II and III (American Joint Committee on Cancer, AJCC staging) primary CRCs, were followed prospectively for a median time of 31 months (January 2006 to December 2009). All patients were assessed, operated and clinically followed. Tumour samples were obtained for cytopathological verification and MSI grading. Results: Of the 125 patients, 21 (20%) had high MSI (MSI-H), and 101 patients (80%) had MSI-L or MSS (low frequency MSI or stable MSI). Patients with MSS CRC were more likely to have recurrent disease (P=0.03; OR=3.2; CI 95% 1-10.2) compared to those with MSI-H CRC. Multi- and univariate Cox regression analysis failed to show a difference between MSI-H and MSS groups with respect to disease-free, disease-specific and overall survival. However, the disease-free survival was significantly lower in patients with MSI-H CRC treated by adjuvant 5-FU therapy (P=0.03). Interpretation & conclusions: MSI-H CRCs had a lower recurrence rate, but the prognosis was worse following adjuvant 5-FU therapy. PMID:27748284

  9. CHEMICAL INTERACTIONS OF ARSENATE, ARSENITE, PHOSPHATE, AND SILICATE WITH IRON (II,III) HYDROXYCARBONATE GREEN RUST

    EPA Science Inventory

    Granular zerovalent iron has been proposed to be used as a medium in permeable reactive barriers (PRBs) to remove arsenic from contaminated groundwater. Iron(II, III) hydroxycarbonate green rust (carbonate green rust, or CGR) is a major corrosion product of zerovalent iron under ...

  10. Aging and Surveillance Program MINUTEMAN II/III Stage II Program Progress.

    DTIC Science & Technology

    1985-11-01

    130 Firing Adapters Used to Fire VECP Igniters 58 132 Squib Arrangement Used in Both KR80000 Safe and Arm and FFTFs 59 133 Bladder Permeation vs Age...hydrolytic liner degradation as the primary mechanism leading ; . " to failure for the motor. Kinetic projections for service life ranged from 14 to 17...the igniter following assembly . In general, propellant in the bulk of the web is slightly harder than that measured in the fin. Propellant in the slot

  11. Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

    ClinicalTrials.gov

    2017-03-06

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  12. Bevacizumab, Fluorouracil, Leucovorin Calcium, and Oxaliplatin Before Surgery in Treating Patients With Stage II-III Rectal Cancer

    ClinicalTrials.gov

    2015-10-24

    Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Rectum; Stage IIA Rectal Cancer; Stage IIB Rectal Cancer; Stage IIC Rectal Cancer; Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer

  13. Multiparametric MRI-based differentiation of WHO grade II/III glioma and WHO grade IV glioblastoma

    PubMed Central

    Wiestler, Benedikt; Kluge, Anne; Lukas, Mathias; Gempt, Jens; Ringel, Florian; Schlegel, Jürgen; Meyer, Bernhard; Zimmer, Claus; Förster, Stefan; Pyka, Thomas; Preibisch, Christine

    2016-01-01

    Non-invasive, imaging-based examination of glioma biology has received increasing attention in the past couple of years. To this end, the development and refinement of novel MRI techniques, reflecting underlying oncogenic processes such as hypoxia or angiogenesis, has greatly benefitted this research area. We have recently established a novel BOLD (blood oxygenation level dependent) based MRI method for the measurement of relative oxygen extraction fraction (rOEF) in glioma patients. In a set of 37 patients with newly diagnosed glioma, we assessed the performance of a machine learning model based on multiple MRI modalities including rOEF and perfusion imaging to predict WHO grade. An oblique random forest machine learning classifier using the entire feature vector as input yielded a five-fold cross-validated area under the curve of 0.944, with 34/37 patients correctly classified (accuracy 91.8%). The most important features in this classifier as per bootstrapped feature importance scores consisted of standard deviation of T1-weighted contrast enhanced signal, maximum rOEF value and cerebral blood volume (CBV) standard deviation. This study suggests that multimodal MRI information reflects underlying tumor biology, which is non-invasively detectable through integrative data analysis, and thus highlights the potential of such integrative approaches in the field of radiogenomics. PMID:27739434

  14. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... the end box and maintain the temperature of the aqueous liquid below its boiling point, maintain a... its boiling point. 9. Open-top containers holding liquid mercury Maintain a layer of aqueous liquid... with smooth interiors and adequate low point drains or mercury knock-out pots to avoid liquid...

  15. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... the end box and maintain the temperature of the aqueous liquid below its boiling point, maintain a... its boiling point. 9. Open-top containers holding liquid mercury Maintain a layer of aqueous liquid... with smooth interiors and adequate low point drains or mercury knock-out pots to avoid liquid...

  16. Current Advancement in Multidisciplinary Treatment for Resectable cStage II/III Esophageal Squamous Cell Carcinoma in Japan

    PubMed Central

    Matsuda, Satoru; Kawakubo, Hirofumi; Ando, Nobutoshi; Kitagawa, Yuko

    2016-01-01

    Multidisciplinary treatment comprising surgery, chemotherapy, and radiotherapy for resectable esophageal squamous cell carcinoma (ESCC) is widely used with improved prognosis. Transthoracic esophagectomy (TTE) with extended lymph node (LN) dissection, known as three field LN dissection, has been recommended for ESCC using open thoracotomy or the thoracoscopic approach. The Japan Clinical Oncology Group (JCOG) trial (JCOG1409) is investigating the patients’ long term survival using the thoracoscopic approach that has been shown to reduce the incidence of postoperative respiratory complication. For perioperative treatment, neoadjuvant chemotherapy using cisplatin plus 5-fluorouracil (5-FU), has been accepted as the standard of care in Japan based on the JCOG9907 trial. In Western countries, neoadjuvant chemoradiotherapy was shown to prolong overall survival for esophageal cancer, including ESCC. Although surgery has been recognized as an initial curative treatment for esophageal cancer, definitive chemoradiotherapy is an alternative treatment for patients who are unable to undergo thoracotomy or who decline to undergo surgery. This article reviews multidisciplinary treatment advances for ESCC. However, current standard treatments are country dependent and the ongoing trial may help standardize ESCC treatment across various societies. PMID:27384595

  17. Intramolecular electronic couplings in class II/III organic mixed-valence systems of bis(1,4-dimethoxybenzene).

    PubMed

    Yang, Juanhua; Zhang, Weiwei; Si, Yubing; Zhao, Yi

    2012-12-06

    The intramolecular electronic couplings in organic mixed-valence systems [D-(ph)(n)-D](•+) (D = 2,5-dimethoxy-4-methylphenyl, n = 0, 1, and 2) are calculated by dominantly using density functional theory to investigate their dependence of functionals. Since these systems have the property that the charge is from localization to delocalization, the optimized structures are sensitive to the functionals. The geometric optimizations show that CAM-B3LYP and ωB97X-D functionals are good choices for delocalized systems and LC-ωPBE and M06HF are suitable for the systems from charge almost localization to localization. The calculations of electronic couplings demonstrate that the pure functional generally underestimates the electronic couplings whereas the pure HF overestimates them. Furthermore, the electronic couplings from the conventional generalized Mulliken-Hush method are very sensitive to the HF component in functionals, which makes it a challenge to accurately estimate the values. A new reduced two-state method is thus proposed to overcome the deficiency, and the obtained electronic couplings are less sensitive to the ω value in LC-ω PBE functional and they are also consistent with the experimental data.

  18. Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

    PubMed Central

    Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

    2016-01-01

    Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

  19. Vaccine Therapy and Cyclophosphamide in Treating Patients With Stage II-III Breast or Stage II-IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-10-10

    Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIA Breast Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Breast Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Breast Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Breast Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Breast Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  20. Chlorine and temperature directed self-assembly of Mg-Ru2(ii,iii) carbonates and particle size dependent magnetic properties.

    PubMed

    Yang, Jian-Hui; Cheng, Ru-Mei; Jia, Yan-Yan; Jin, Jin; Yang, Bing-Bing; Cao, Zhi; Liu, Bin

    2016-02-21

    A series of heterometallic magnesium diruthenium(ii,iii) carbonates, namely K{Mg(H2O)6}2[Ru2(CO3)4Cl2]·4H2O (1), K2[{Mg(H2O)4}2Ru2(CO3)4(H2O)Cl]Cl2·2H2O (2), K[Mg(H2O)5Ru2(CO3)4]·5H2O (3) and K[Mg(H2O)4Ru2(CO3)4]·H2O (4), were synthesized from the reaction of Ru2(CO3)4(3-) and Mg(2+) in aqueous solution. Compound 1 is composed of ionic crystals with the Ru2(CO3)4Cl2(5-) : Mg(H2O)6(2+) : K(+) ratio of 1 : 2 : 1. Compound 2 consists of two dimensional layer structures, in which each octahedral environment Mg(H2O)4(2+) bonds to two [Ru2(CO3)4(H2O)Cl](4-) units in a cis manner forming a neutral square-grid layer {Mg(H2O)4Ru2(CO3)4(H2O)Cl}n. For compound 3, one water molecule of each Mg(H2O)6(2+) is substituted by an oxygen atom of Ru2(CO3)4(3-) forming [Mg(H2O)5Ru2(CO3)4](-), and then the neighboring Ru2 dimers are linked together by the rest of the two oxygen atoms of carbonates to form a layer structure {Mg(H2O)5Ru2(CO3)4}n(n-). In compound 4, the neighboring squared-grid layers {Ru2(CO3)4}n(3n-), similar to those in compound 3, are linked by each octahedral environment Mg(H2O)4(2+) in a cis manner forming the three-dimensional network {Mg(H2O)4Ru2(CO3)4}n(n-). Compound 3 shows ferromagnetic coupling between Ru2 dimers, and a long-range ordering is observed below 3.8 K. Compound 4 displays a magnetic ordering below 3.5 K, and a systematic study of the size-dependent magnetic properties of compound 4 reveals that the coercivity of 4 has been improved with reduced sample particle size from the micrometer to the nanometer scale.

  1. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell... that you cannot repair the leaking equipment without taking the cell off line, provided that you contain the dripping mercury at all times as described above, and take the cell off line as soon...

  2. Transthoracic versus abdominal-transhiatal resection for treating Siewert type II/III adenocarcinoma of the esophagogastric junction: a meta-analysis

    PubMed Central

    Zheng, Zhi; Cai, Jun; Yin, Jie; Zhang, Jun; Zhang, Zhong-Tao; Wang, Kang-Li

    2015-01-01

    Our study aimed to explore the differences in short and long-term outcomes about the transthoracic (TH) and abdominal-transhiatal (TH) approaches for treating esophagogastric junction (AEG). A systematic review of PubMed, EMbase, Cochrane Library, China National Knowledge Infrastructure and CBMdisc was performed. All original articles comparing TH with TA were included in the study. Meta-analysis was conducted using odd ratios (OR) and weighted mean differences (WMDs).Thirteen studies including 2489 patients with adenocarcinoma of the esophagogastric junction, with 1050 patients underwent TA and 1437 patients underwent TH were pooled for this study. There were no significant difference between two approaches concerning duration of operation, blood loss, anastomotic leakage and positive of proximal incisal margin. Lymph node excised also showed no significant differences between two procedures in RCTs while in TA group of Non-RCTs, the number of lymph node dissection is higher. TH approach was associated with a longer length of hospital stay and had higher incidence of respiratory and cardiovascular complications and early postoperative mortality. Overall analysis of 1, 3, 5-year survival showed no significant difference between two approaches. Based on the study, TA approach had a positive impact than TH for AEG with respect to respiratory and cardiovascular complications, hospital stay and early mortality rates. There were no significant differences between the two approaches for long-term survival. Therefore, two surgical approaches are acceptable, and the elders with poor cardiopulmonary function, we recommended TA approach for treating it. PMID:26770310

  3. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study

    PubMed Central

    2014-01-01

    Aim This study was designed to evaluate the efficacy and toxicities of concomitant boost intensity-modulated radiation therapy (IMRT) along with capecitabine and oxaliplatin, followed by a cycle of Xelox, in neoadjuvant course for locally advanced rectal cancer. Materials and methods Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received IMRT to the pelvis of 50 Gy and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). One cycle of Xelox (oxaliplatin 130 mg/m2 on d1 and capecitabine 1000 mg/m2 twice daily d1–14) was given two weeks after the completion of chemoradiation, and radical surgery was scheduled eight weeks after chemoradiation. Tumor response was evaluated by tumor regression grade (TRG) system and acute toxicities were evaluated by NCI-CTC 3.0 criteria. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test. Results A total of 78 patients were included between March 2009 and May 2011 (median age 54 years; 62 male). Seventy-six patients underwent surgical resection. Twenty-eight patients underwent sphincter-sparing lower anterior resection and 18 patients (23.7%) were evaluated as pathological complete response (pCR). The incidences of grade 3 hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively. The three-year LR (local recurrence), DFS (disease-free survival) and OS (overall survival) rates were 14.6%, 63.8% and 77.4%, respectively. Initial clinical T stage and tumor regression were independent prognostic factors to DFS. Conclusion An intensified regimen of concomitant boost radiotherapy plus concurrent capecitabine and oxaliplatin, followed by one cycle of Xelox, can be safely administered in patients with locally advanced rectal cancer, and produces a high rate of pCR. A prognostic score model is helpful to distinguish different long-term prognosis groups in early stage. PMID:24606870

  4. Whole genome sequencing of a recombinant type II/III Toxoplasma gondii strain from Uganda reveals chromosome sorting and local allelic variants.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toxoplasma gondii is a zoonotic parasite of global importance. In common with many protozoan parasites it has the capacity for sexual recombination, but current evidence suggests this is rarely employed. The global population structure is dominated by a small number of clonal genotypes, which exhib...

  5. Two-staged revision with custom made prosthesis in septic failure of massive allograft reconstruction after type II-III pelvic resection.

    PubMed

    Bekmez, Senol; Ayvaz, Mehmet; Mermerkaya, M Uğur; Tokgozoglu, A Mazhar

    2014-01-01

    Reconstruction of defects occurring during periacetabular resections of pelvic tumors is required particularly in young and functionally active persons. Allograft reconstruction provides good functional outcomes in restoration of normal pelvic anatomy. A 24-year-old male patient was reconstructed with an allograft-prosthesis composite after periacetabular resection due to pelvic chondrosarcoma. After four years, a two-staged revision with a custom-made pelvic prosthesis was performed due to septic failure. Successful radiographic and functional outcomes were achieved at two-year follow-up. In conclusion, we suggest a two-staged revision with a custom-made pelvic prosthesis as a satisfactory option in case of septic failure of allograft reconstruction after periacetabular resection.

  6. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer†

    PubMed Central

    O'Neil, B. H.; Scott, A. J.; Ma, W. W.; Cohen, S. J.; Aisner, D. L.; Menter, A. R.; Tejani, M. A.; Cho, J. K.; Granfortuna, J.; Coveler, L.; Olowokure, O. O.; Baranda, J. C.; Cusnir, M.; Phillip, P.; Boles, J.; Nazemzadeh, R.; Rarick, M.; Cohen, D. J.; Radford, J.; Fehrenbacher, L.; Bajaj, R.; Bathini, V.; Fanta, P.; Berlin, J.; McRee, A. J.; Maguire, R.; Wilhelm, F.; Maniar, M.; Jimeno, A.; Gomes, C. L.; Messersmith, W. A.

    2015-01-01

    Background Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Materials and methods Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 weekly for 3 weeks in a 4-week cycle (GEM). Results A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85–1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68–1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. Conclusions The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation. PMID:26091808

  7. Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-12-21

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  8. Akt Inhibitor MK-2206 and Anastrozole With or Without Goserelin Acetate in Treating Patients With Stage II-III Breast Cancer

    ClinicalTrials.gov

    2016-12-26

    Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  9. Electron transfer rate on mixed valence states of Class II/III transition for N, N'-diphenyl-1,4-phenylenediamine structures as a polyaniline unit

    NASA Astrophysics Data System (ADS)

    Nishiumi, Toyohiko; Nomura, Yasuhiro; Higuchi, Masayoshi; Yamamoto, Kimihisa

    2003-08-01

    The first example of the determination of the electron transfer rate ( λ, V, Δ G*, kth) for N, N'-diphenyl-1,4-phenylenediamine derivatives using the Marcus-Hush theory is described. These results were in good agreement with the ones obtained using variable-temperature IR spectra measurements.

  10. 7Li and 14N NMR studies of phase II-III transition in LiNH4SO4 single crystals

    NASA Astrophysics Data System (ADS)

    Lim, Ae Ran

    2016-12-01

    The NMR spectra of 7Li and 14N nuclei in LiNH4SO4 crystals were obtained near the phase transition temperature TC2=284.5 K. Below TC2, the two physically inequivalent Li groups in phase III were distinguished in 7Li NMR spectra. Meanwhile, the 14N NMR spectra in phase II above TC2 showed four pairs of lines, where as those in phase III showed eight pairs. These changes in the resonance frequencies near TC2 were attributed to the structural phase transition. The 7Li and 14N nuclei in the structure are coordinated through the Li-O-H-N skeleton. Therefore, changes in their NMR spectra with temperature are correlated. The displacements of 7Li and 14N in LiNH4SO4 crystals play important roles in the phase transition near TC2.

  11. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.

    PubMed

    Weller, Michael; Weber, Ruthild G; Willscher, Edith; Riehmer, Vera; Hentschel, Bettina; Kreuz, Markus; Felsberg, Jörg; Beyer, Ulrike; Löffler-Wirth, Henry; Kaulich, Kerstin; Steinbach, Joachim P; Hartmann, Christian; Gramatzki, Dorothee; Schramm, Johannes; Westphal, Manfred; Schackert, Gabriele; Simon, Matthias; Martens, Tobias; Boström, Jan; Hagel, Christian; Sabel, Michael; Krex, Dietmar; Tonn, Jörg C; Wick, Wolfgang; Noell, Susan; Schlegel, Uwe; Radlwimmer, Bernhard; Pietsch, Torsten; Loeffler, Markus; von Deimling, Andreas; Binder, Hans; Reifenberger, Guido

    2015-05-01

    Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

  12. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor...

  13. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor...

  14. Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

    ClinicalTrials.gov

    2017-01-19

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  15. Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer

    ClinicalTrials.gov

    2017-01-31

    Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

  16. Comparative effectiveness of combined therapy inhibiting EGFR and VEGF pathways in patients with advanced non-small-cell lung cancer: a meta-analysis of 16 phase II/III randomized trials

    PubMed Central

    Cai, Shangli; Wu, Tongwei; Yan, Guangyue; Cheng, Sijin; Cui, Kang; Xi, Ying; Qi, Xiaolong; Zhang, Jie; Ma, Wang

    2017-01-01

    Background & Aims Combined therapy inhibiting EGFR and VEGF pathways is becoming a promising therapy in the treatment of advanced non-small-cell lung cancer (NSCLC), however, with controversy. The study aims to compare the efficacy of combined inhibition therapy versus control therapy (including placebo, single EGFR inhibition and single VEGF inhibition) in patients with advanced NSCLC. Materials and Methods An adequate literature search in EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was conducted. Phase II or III randomized controlled trials (RCTs) that compared effectiveness between combined inhibition therapy and control therapy in patients with advanced NSCLC were eligible. The endpoint was overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results Sixteen phase II or III RCTs involving a total of 7,109 patients were included. The results indicated that the combined inhibition therapy significantly increased the ORR (OR = 1.59, 95% CI = 1.36-1.87, p<0.00001; I2 = 36%) when compared to control therapy. In the subgroup analysis, the combined inhibition therapy clearly increased the ORR (OR = 2.04, 95% CI = 1.60-2.60, p<0.00001; I2 = 0%) and improved the PFS (HR = 0.78, 95% CI = 0.71-0.85, p<0.00001;I2 = 0%) when compared with the placebo, and similar results was detected when compared with the single EGFR inhibition in terms of ORR (OR = 1.39, 95% CI = 1.12-1.74, p = 0.003; I2 = 30%) and PFS (HR = 0.73, 95% CI = 0.67-0.81, p<0.0001; I2 = 50%). No obvious difference was found between the combined inhibition therapy and single VEGF inhibition in term of ORR, however, combined inhibition therapy significantly decreased the PFS when compared to the single VEGF inhibition therapy (HR = 1.70, 95% CI = 1.34-2.17, p<0.0001; I2 = 50%). Besides, no significant difference was observed between the combined inhibition therapy and control therapy in term of OS (including placebo, single EGFR inhibition and single VEGF inhibition) (HR = 0.98, 95% CI = 0.92-1.04, p = 0.41; I2 = 0%). Conclusions Combined inhibition therapy was superior to placebo and single EGFR inhibition in terms of ORR, PFS for advanced NSCLC, however, no statistical difference were found in term of OS. Besides, combined inhibition therapy was not superior to single VEGF inhibition in terms of ORR, PFS and OS. Therefore, combined inhibition therapy is recommended to treat advanced NSCLC patients. PMID:27690345

  17. Twelve-week, multicenter, placebo-controlled, randomized, double-blind, parallel-group, comparative phase II/III study of benzoyl peroxide gel in patients with acne vulgaris: A secondary publication.

    PubMed

    Kawashima, Makoto; Sato, Shinichi; Furukawa, Fukumi; Matsunaga, Kayoko; Akamatsu, Hirohiko; Igarashi, Atsuyuki; Tsunemi, Yuichiro; Hayashi, Nobukazu; Yamamoto, Yuki; Nagare, Toshitaka; Katsuramaki, Tsuneo

    2017-03-11

    A placebo-controlled, randomized, double-blind, parallel-group, comparative, multicenter study was conducted to investigate the efficacy and safety of benzoyl peroxide (BPO) gel, administrated once daily for 12 weeks to Japanese patients with acne vulgaris. Efficacy was evaluated by counting all inflammatory and non-inflammatory lesions. Safety was evaluated based on adverse events, local skin tolerability scores and laboratory test values. All 609 subjects were randomly assigned to receive the study products (2.5% and 5% BPO and placebo), and 607 subjects were included in the full analysis set, 544 in the per protocol set and 609 in the safety analyses. The median rates of reduction from baseline to the last evaluation of the inflammatory lesion counts, the primary end-point, in the 2.5% and 5% BPO groups were 72.7% and 75.0%, respectively, and were significantly higher than that in the placebo group (41.7%). No deaths or other serious adverse events were observed. The incidences of adverse events in the 2.5% and 5% BPO groups were 56.4% and 58.8%, respectively; a higher incidence than in the placebo group, but there was no obvious difference between the 2.5% and 5% BPO groups. All adverse events were mild or moderate in severity. Most adverse events did not lead to study product discontinuation. The results suggested that both 2.5% and 5% BPO are useful for the treatment of acne vulgaris.

  18. Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin

    PubMed Central

    O'Connell, Michael J.; Lavery, Ian; Yothers, Greg; Paik, Soonmyung; Clark-Langone, Kim M.; Lopatin, Margarita; Watson, Drew; Baehner, Frederick L.; Shak, Steven; Baker, Joffre; Cowens, J. Wayne; Wolmark, Norman

    2010-01-01

    Purpose These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. Patients and Methods We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. Results A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. Conclusion RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study. PMID:20679606

  19. IgE and IgG cross-reactivity among Lol p I and Lol p II/III. Identification of the C-termini of Lol p I, II, and III as cross-reactive structures.

    PubMed

    van Ree, R; van Leeuwen, W A; van den Berg, M; Weller, H H; Aalberse, R C

    1994-04-01

    In this study, the homologous C-termini of Lol p I, Lol p II, and Lol p III were shown to contain cross-reactive B-cell epitopes. This was demonstrated by inhibition studies with purified Lol p I, II, and III and synthetic peptides of their C-termini. It was ruled out that the observed cross-reactivity was caused by cross-contamination of the purified allergens. Both human IgE and IgG bound to the C-terminus of Lol p I. These antibodies were cross-reactive with Lol p II and, more specifically, with its C-terminus. Within a small panel of allergic patients, no cross-reactivity with Lol p III was found. A hyperimmune polyclonal rabbit antiserum against Lol p I also recognized the Lol p I C-terminus. As for human antibodies, cross-reactivity with Lol p II and its C-terminus was demonstrated. Cross-reactivity with Lol p III was demonstrated with C-terminal peptides, but not with native Lol p III. A polyclonal rabbit antiserum against Lol p II bound to the C-terminal peptides of both Lol p II and III. This binding was inhibited with Lol p I, confirming that cross-reactive structures exist not only on the C-termini of Lol p II and Lol p I, but also of Lol p III and Lol p I. The existence of cross-reactivity between Lol p I and Lol p II and III possibly contributes to the frequently observed cosensitization for these allergens in grass-pollen-allergic patients.

  20. Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-07

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  1. Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition.

    PubMed

    Qian, Yi; van Meel, Eline; Flanagan-Steet, Heather; Yox, Alex; Steet, Richard; Kornfeld, Stuart

    2015-01-30

    UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. GNPTAB encodes the α and β subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III αβ. Prior investigation of missense mutations in GNPTAB uncovered amino acids in the N-terminal region and within the DMAP domain involved in Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Here, we undertook a comprehensive analysis of the remaining missense mutations in GNPTAB reported in mucolipidosis II and III αβ patients using cell- and zebrafish-based approaches. We show that the Stealth domain harbors the catalytic site, as some mutations in these regions greatly impaired the activity of the enzyme without affecting its Golgi localization and proteolytic processing. We also demonstrate a role for the Notch repeat 1 in lysosomal hydrolase recognition, as missense mutations in conserved cysteine residues in this domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases. Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. Finally, the mutant R587P, located in the spacer between Notch 2 and DMAP, was partially rescued by overexpression of the γ subunit, suggesting a role for this region in γ subunit binding. These studies provide new insight into the functions of the different domains of the α and β subunits.

  2. Evidence-based nutritional recommendations for the prevention and treatment of overweight and obesity in adults (FESNAD-SEEDO consensus document). The role of diet in obesity prevention (II/III).

    PubMed

    Gargallo Fernández, M; Quiles Izquierdo, J; Basulto Marset, J; Breton Lesmes, I; Formiguera Sala, X; Salas-Salvadó, J

    2012-01-01

    This study is a consensus document of two Spanish scientific associations, FESNAD (Spanish Federation of Nutrition, Food and Dietetetic Associations) and SEEDO (Spanish Association for the Study of Obesity), about the role of the diet in the prevention and of overweight and obesity in adults. It is the result of a careful and systematic review of the data published in the medical literature from January 1st 1996 to January 31st 2011 concerning the role of the diet on obesity prevention. The conclusions obtained have been classified according several evidence levels. Subsequently, in agreement with these evidence levels, different degree recommendations are established. These recommendations could be potentially useful to design food guides as part of strategies to prevent overweight and obesity.

  3. REVIEW OF THE NEGOTIATION OF THE MODEL PROTOCOL ADDITIONAL TO THE AGREEMENT(S) BETWEEN STATE(S) AND THE INTERNATIONAL ATOMIC ENERGY AGENCY FOR THE APPLICATION OF SAFEGUARDS, INFCIRC/540 (Corrected) VOLUME II/III IAEA COMMITTEE 24, Major Issues Underlying the Model Additional Protocol (1996-1997).

    SciTech Connect

    Rosenthal, M.D.; Saum-Manning, L.; Houck, F.

    2010-01-01

    Volume I of this Review traces the origins of the Model Additional Protocol. It covers the period from 1991, when events in Iraq triggered an intensive review of the safeguards system, until 1996, when the IAEA Board of Governors established Committee 24 to negotiate a new protocol to safeguards agreement. The period from 1991-1996 set the stage for this negotiation and shaped its outcome in important ways. During this 5-year period, many proposals for strengthening safeguards were suggested and reviewed. Some proposals were dropped, for example, the suggestion by the IAEA Secretariat to verify certain imports, and others were refined. A rough consensus was established about the directions in which the international community wanted to go, and this was reflected in the draft of an additional protocol that was submitted to the IAEA Board of Governors on May 6, 1996 in document GOV/2863, Strengthening the Effectiveness and Improving the Efficiency of the Safeguards System - Proposals For Implementation Under Complementary Legal Authority, A Report by the Director General. This document ended with a recommendation that, 'the Board, through an appropriate mechanism, finalize the required legal instrument taking as a basis the draft protocol proposed by the Secretariat and the explanation of the measures contained in this document.'

  4. 77 FR 27272 - Environmental Impact Statement: Hamilton and Clermont Counties, OH

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-09

    ... Segment 3 of the proposed Oasis Rail Line which would share the right-of-way with relocated SR-32. Tier 1... proposed Segments II-III SR 32 project and proposed Oasis Rail Line Segment 3 will involve more detailed... Oasis rail transit (a portion of which parallels the Segment II-III corridor), a ] multi-modal...

  5. Interleukin-1 Blockade With Canakinumab to Improve Exercise Capacity in Patients With Chronic Systolic Heart Failure and Elevated High Sensitivity C-reactive Protein (Hs-CRP)

    ClinicalTrials.gov

    2016-08-22

    Prior Acute Myocardial Infarction; Evidence of Systemic Inflammation (C Reactive Protein Plasma >2 mg/l); Reduced Left Ventricle Ejection Fraction (<50%); Symptoms of Heart Failure (NYHA Class II-III)

  6. Is obesity stigmatizing? Body weight, perceived discrimination, and psychological well-being in the United States.

    PubMed

    Carr, Deborah; Friedman, Michael A

    2005-09-01

    We investigate the frequency and psychological correlates of institutional and interpersonal discrimination reported by underweight, normal weight, overweight, obese I, and obese II/III Americans. Analyses use data from the Midlife Development in the United States study, a national survey of more than 3,000 adults ages 25 to 74 in 1995. Compared to normal weight persons, obese II/III persons (body mass index of 35 or higher) are more likely to report institutional and day-to-day interpersonal discrimination. Among obese II/III persons, professional workers are more likely than nonprofessionals to report employment discrimination and interpersonal mistreatment. Obese II/III persons report lower levels of self-acceptance than normal weight persons, yet this relationship is fully mediated by the perception that one has been discriminated against due to body weight or physical appearance. Our findings offer further support for the pervasive stigma of obesity and the negative implications of stigmatized identities for life chances.

  7. Chronic shin splints. Classification and management of medial tibial stress syndrome.

    PubMed

    Detmer, D E

    1986-01-01

    A clinical classification and treatment programme has been developed for chronic medial tibial stress syndrome. Medial tibial stress syndrome has been reported to be either tibial stress fracture or microfracture, tibial periostitis, or distal deep posterior chronic compartment syndrome. Three chronic types exist and may coexist: Type I (tibial microfracture, bone stress reaction or cortical fracture); type II (periostalgia from chronic avulsion of the periosteum at the periosteal-fascial junction); and type III (chronic compartment syndrome syndrome). Type I disease is treated nonoperatively. Operations for resistant types II and III medial tibial stress syndrome were performed in 41 patients. Bilaterality was common (type II, 50% type III, 88%). Seven had coexistent type II/III; one had type I/II. Preoperative symptoms averaged 24 months in type II, 6 months in type III, and 33 months in types II/III. Mean age was 22 years (15 to 51). Resting compartment pressures were normal in type II (mean 12 mm Hg) and elevated in type III and type II/III (mean 23 mm Hg). Type II and type II/III patients received fasciotomy plus periosteal cauterisation. Type III patients had fasciotomy only. All procedures were performed on an outpatient basis using local anaesthesia. Follow up was complete and averaged 6 months (2 to 14 months). Improved performance was as follows: type II, 93%, type III, 100%; type II/III, 86%. Complete cures were as follows: type II, 78%; type III, 75%; and type II/III, 57%. This experience suggests that with precise diagnosis and treatment involving minimal risk and cost the athlete has a reasonable chance of return to full activity.

  8. Cognitive Effort and Decision Making Strategies: A Componential Analysis of Choice.

    DTIC Science & Technology

    1986-07-31

    COMPONENTIAL ANALYSIS OF CHOICE(U) DUKE UNIV DURNA NC J R DETTNAN ET AL. 31 JUL 86 RR-96-2 NSWI4-6S-C- S ±14 UNCLASSIFIED F/O 5/𔃻@ M IIIII IIIII1 0 5...CLASSIFICATION OF THIS PAGE M%0on DOM Entored) REPORT DOCUMENTATION PAGE BEFRED COMLEIGM 1. REPORT NUMBER G2. OVT ACCES&ION NO S . RECIPIENT’S CATALOG...NUMBER86-2 D /4CJ 4. TITLE (and Subtitle) S . TYPE OF REPORT & PERIOD COVERED COGNITIVE EFFORT AND DECISION MAKING STRATEGIES: Research A COMPONENTIAL

  9. Balancing Accession and Retention: The Disaggregate Model.

    DTIC Science & Technology

    1982-08-01

    MENDEZ ET AL. AUG 82 CNA- PP -374 UNCLSSIFIED N80814-76-C -888i F/G 5/9 N IIIII._____ m~j~2 111112.2 11.6 140 1111120 1II’.8 IIIII 25 11 A1. 1.6 MICROCOPY...Introduction ...........00........ . 00.. . ..... 0............ .0 .1 ;.The Modelo ... ... ... .... ... ... ... o................ ... ..... - 2 The Flow of...34 by Matthew S. Goldberg and Michael F. Hager, Unclassified, 10 June 1981 K -1 .1 I LI -- 4 .1 CNA PROFESSIDNL PAPS - 1978 ID RFlSENT" PP 211 PP 222

  10. Cluster of infections caused by methicillin-resistant Staphylococcus pseudintermedius in humans in a tertiary hospital.

    PubMed

    Starlander, Gustaf; Börjesson, Stefan; Grönlund-Andersson, Ulrika; Tellgren-Roth, Christian; Melhus, Asa

    2014-08-01

    The dog-associated Staphylococcus pseudintermedius is a rare pathogen in humans. Here we describe a cluster of infections caused by the methicillin-resistant S. pseudintermedius clone ST71-J-t02-II-III. It involved four elderly patients at a tertiary hospital. Three patients had wound infections, and the strain had a tendency to cause bullous skin lesions.

  11. Dendrites and Cognition: A Negative Pilot Study in the Rat.

    ERIC Educational Resources Information Center

    Anderson, Britt

    1995-01-01

    The dendritic structure of layer II-III pyramidal neurons of the parietal cortex in 41 Long-Evans rats was compared to behavioral assessments of attention to novelty, response flexibility, and reasoning. A significant correlation between dendritic arborization and behavioral performance was not demonstrated. (SLD)

  12. Mediterranean and Black Sea organisms and algae from mariculture as sources of antitumor drugs.

    PubMed

    Apryshko, Galina N; Ivanov, Valeriy N; Milchakova, Natalya A; Nekhoroshev, Mikhail V

    2005-06-01

    Mussels and tunicates cultivated in Mediterranean and Black Sea are the sources of antitumor drugs. Three compounds isolated from these animals (ET-743, aplidin and bryostatin-1) are on the II-III stages of clinical trials. Carotenoid fucoxantin that is present in edible brown algae possesses antitumor activity. The consumption of brown macrophyts decreases the risk of cancer development.

  13. Evidence of nosocomial transmission of human rhinovirus in a neonatal intensive care unit.

    PubMed

    Reese, Sara M; Thompson, Meredyth; Price, Connie S; Young, Heather L

    2016-03-01

    Nosocomial respiratory infections cause significant morbidity and mortality, especially among the extremely susceptible neonatal population. Human rhinovirus C is a common viral respiratory illness that causes significant complications in children <2 years old. We describe a nosocomial outbreak of human rhinovirus C in a level II-III neonatal intensive care unit in an urban public safety net hospital.

  14. US EPA, Pesticide Product Label, , 02/22/1974

    EPA Pesticide Factsheets

    2011-04-14

    ... lll'd ,trip' in Ihl' fi,'ld. hp,',ien<,' h •• , ,1111\\1 n Ih.ll lh('m il.11 mi\\ing in Ih(' ,"i I Il(I Ul\\ 10 .I d"plh .IpIIIII\\im.II,'lv unl' ... di ... ( rn~ to " dt'plh 01 loUr IIH IH· .... ...

  15. 77 FR 18793 - Spectrum Sharing Innovation Test-Bed Pilot Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-28

    ... National Telecommunications and Information Administration Spectrum Sharing Innovation Test-Bed Pilot... conduct in Phase II/III of the Spectrum Sharing Innovation Test-Bed pilot program to assess whether... Communications Commission (FCC) and other federal agencies, established a Spectrum Sharing Innovation...

  16. CORRIGENDUM: Optical and electronic properties of ZnO:P/n+-Si heterostructures fabricated by metalorganic chemical vapour deposition

    NASA Astrophysics Data System (ADS)

    Zhu, H.; Du, G.; Li, X.; Zhang, Y.; Cui, Y.; Huang, K.; Xia, X.; Yang, T.; Zhang, B.; Chang, Y.

    2007-04-01

    There is a mistake in the first sentence of the paper, where 'II-III' should read as 'II-IV'. The corrected sentence is: Zinc oxide (ZnO) is a II-IV compound semiconductor with a hexagonal wurtzite-type crystal structure.

  17. Is Obesity Stigmatizing? Body Weight, Perceived Discrimination, and Psychological Well-Being in the United States

    ERIC Educational Resources Information Center

    Carr, Deborah; Friedman, Michael A.

    2005-01-01

    We investigate the frequency and psychological correlates of institutional and interpersonal discrimination reported by underweight, normal weight, overweight, obese I, and obese II/III Americans. Analyses use data from the Midlife Development in the United States study, a national survey of more than 3,000 adults ages 25 to 74 in 1995. Compared…

  18. A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions.

    PubMed

    Wzorek, Joseph S; Knöpfel, Thomas F; Sapountzis, Ioannis; Evans, David A

    2012-12-07

    A new approach to the tetracycline core structure is presented. The pivotal intermediate is identified as macrocycle III. The two interior bonds (C4a-C12a and C5a-C11a) are to be constructed through sequential transannular Michael additions (III-II) and compression-promoted transannular isoxazole alkylations from intermediate II.

  19. Symmetrical osteoporosis (spongy hyperostosis) in a prehistoric skull from New Mexico.

    PubMed

    Jarcho, S; Simon, N; Jaffe, H L

    1965-01-01

    Fragments of an Anasazi skull (Pueblo II-III) from New Mexico are described. Lesions of symmetrical osteoporosis were found and their anatomical and roentgenographic characteristics are discussed. The term symmetrical osteoporosis has led to confusion with the unrelated disease osteoporosis and should be replaced by the designation spongy hyperostosis.

  20. Greenhouse evaluation of commercial soybean cultivars adapted to the northern United States for resistance to charcoal rot

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Thirty (30) and sixty-seven (67) commercially available soybean (Glycine max (L.) Merr) cultivars from Wisconsin (Maturity group (MG) I-II) and Indiana (MG II-III), respectively, were evaluated for charcoal rot (CR; Macrophomina phaseolina (Tassi) Goid) resistance using a cut-stem greenhouse assay. ...

  1. 10 CFR 50.72 - Immediate notification requirements for operating nuclear power reactors.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... cases within one hour of the occurrence of any deviation from the plant's Technical Specifications..., within four hours of the occurrence of any of the following: (i) The initiation of any nuclear plant shutdown required by the plant's Technical Specifications. (ii)-(iii) (iv)(A) Any event that results...

  2. 10 CFR 50.72 - Immediate notification requirements for operating nuclear power reactors.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... cases within one hour of the occurrence of any deviation from the plant's Technical Specifications..., within four hours of the occurrence of any of the following: (i) The initiation of any nuclear plant shutdown required by the plant's Technical Specifications. (ii)-(iii) (iv)(A) Any event that results...

  3. 10 CFR 50.72 - Immediate notification requirements for operating nuclear power reactors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... cases within one hour of the occurrence of any deviation from the plant's Technical Specifications..., within four hours of the occurrence of any of the following: (i) The initiation of any nuclear plant shutdown required by the plant's Technical Specifications. (ii)-(iii) (iv)(A) Any event that results...

  4. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

    PubMed

    Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-03-01

    HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society

  5. Proton Beam Therapy of Stage II and III Non-Small-Cell Lung Cancer

    SciTech Connect

    Nakayama, Hidetsugu; Satoh, Hiroaki; Sugahara, Shinji; Kurishima, Koichi; Tsuboi, Koji; Sakurai, Hideyuki; Ishikawa, Shigemi; Tokuuye, Koichi

    2011-11-15

    Purpose: The present retrospective study assessed the role of proton beam therapy (PBT) in the treatment of patients with Stage II or III non-small-cell lung cancer who were inoperable or ineligible for chemotherapy because of co-existing disease or refusal. Patients and Methods: Between November 2001 and July 2008, PBT was given to 35 patients (5 patients with Stage II, 12 with Stage IIIA, and 18 with Stage IIIB) whose median age was 70.3 years (range, 47.4-85.4). The median proton dose given was 78.3 Gy (range, 67.1-91.3) (relative biologic effectiveness). Results: Local progression-free survival for Stage II-III patients was 93.3% at 1 year and 65.9% at 2 years during a median observation period of 16.9 months. Four patients (11.4%) developed local recurrence, 13 (37.1%) developed regional recurrence, and 7 (20.0%) developed distant metastases. The progression-free survival rate for Stage II-III patients was 59.6% at 1 year and 29.2% at 2 years. The overall survival rate of Stage II-III patients was 81.8% at 1 year and 58.9% at 2 years. Grade 3 or greater toxicity was not observed. A total of 15 patients (42.9%) developed Grade 1 and 6 (17.1%) Grade 2 toxicity. Conclusion: PBT for Stage II-III non-small-cell lung cancer without chemotherapy resulted in good local control and low toxicity. PBT has a definite role in the treatment of patients with Stage II-III non-small-cell lung cancer who are unsuitable for surgery or chemotherapy.

  6. Analysis of pramipexole dose–response relationships in Parkinson’s disease

    PubMed Central

    Wang, Ying; Sun, Sheng-Gang; Zhu, Sui-Qiang; Liu, Chun-Feng; Liu, Yi-Ming; Di, Qing; Shang, Hui-Fang; Ren, Yan; Xiang, Wei; Chen, Sheng-Di

    2017-01-01

    Background Pramipexole (PPX), a non-ergot dopamine receptor agonist, is a first-line treatment for Parkinson’s disease (PD). A critical dose level above which a better benefit-to-harm ratio exists has not been examined. Methods Chinese PD patients (n=464) were retrospectively analyzed by PPX maintenance dose, PD stage, combined levodopa dose, and baseline tremor contribution. The sum score of Baseline Activities of Daily Living (part II) and Motor Examination (III) of the Unified Parkinson’s Disease Rating Scale (UPDRS II+III) was used as a covariate for final score adjustment. Results Sustained-release (SR) and immediate-release (IR) PPX showed similar efficacy based on score changes at 18 weeks, with comparable tolerability. Approximately two-third of patients received PPX at ≥1.5 mg/d, and one fourth of patients had ≥20% tremor contribution to UPDRS II+III. After treatment, patients receiving PPX ≥1.5 mg/d showed better improvement in UPDRS II+III scores (P=0.0025), with similar trends with the IR and SR formulations. Patients with ≥20% tremor contribution showed better improvement in UPDRS II+III scores (P=0.0017). No differences were seen based on PD stage or combined levodopa dose. The overall proportions of adverse events (AEs) were similar. More patients discontinued because of intolerable side effects, and more investigator-defined drug-related AEs were recorded in the <1.5 mg/d subgroup. Conclusion UPDRS II+III improvement was better with PPX ≥1.5 than with <1.5 mg/d in Chinese PD patients after 18 weeks of treatment, with similar trends seen with IR and SR formulations. The frequency of AEs in PPX ≥1.5 and <1.5 mg/d subgroups was similar. PMID:28096656

  7. Fluorescence resonance energy transfer (FRET) indicates that association with the type I ryanodine receptor (RyR1) causes reorientation of multiple cytoplasmic domains of the dihydropyridine receptor (DHPR) α(1S) subunit.

    PubMed

    Polster, Alexander; Ohrtman, Joshua D; Beam, Kurt G; Papadopoulos, Symeon

    2012-11-30

    The skeletal muscle dihydropyridine receptor (DHPR) in the t-tubular membrane serves as the Ca(2+) channel and voltage sensor for excitation-contraction (EC) coupling, triggering Ca(2+) release via the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR). The two proteins appear to be physically linked, and both the α(1S) and β(1a) subunits of the DHPR are essential for EC coupling. Within α(1S), cytoplasmic domains of importance include the I-II loop (to which β(1a) binds), the II-III and III-IV loops, and the C terminus. However, the spatial relationship of these domains to one another has not been established. Here, we have taken the approach of measuring FRET between fluorescent proteins inserted into pairs of α(1S) cytoplasmic domains. Expression of these constructs in dyspedic (RyR1 null) and dysgenic (α(1S) null) myotubes was used to test for function and targeting to plasma membrane/SR junctions and to test whether the presence of RyR1 caused altered FRET. We found that in the absence of RyR1, measureable FRET occurred between the N terminus and C terminus (residue 1636), and between the II-III loop (residue 626) and both the N and C termini; the I-II loop (residue 406) showed weak FRET with the II-III loop but not with the N terminus. Association with RyR1 caused II-III loop FRET to decrease with the C terminus and increase with the N terminus and caused I-II loop FRET to increase with both the II-III loop and N terminus. Overall, RyR1 appears to cause a substantial reorientation of the cytoplasmic α(1S) domains consistent with their becoming more closely packed.

  8. RubisCO of a nucleoside pathway known from Archaea is found in diverse uncultivated phyla in bacteria

    PubMed Central

    Wrighton, Kelly C; Castelle, Cindy J; Varaljay, Vanessa A; Satagopan, Sriram; Brown, Christopher T; Wilkins, Michael J; Thomas, Brian C; Sharon, Itai; Williams, Kenneth H; Tabita, F Robert; Banfield, Jillian F

    2016-01-01

    Metagenomic studies recently uncovered form II/III RubisCO genes, originally thought to only occur in archaea, from uncultivated bacteria of the candidate phyla radiation (CPR). There are no isolated CPR bacteria and these organisms are predicted to have limited metabolic capacities. Here we expand the known diversity of RubisCO from CPR lineages. We report a form of RubisCO, distantly similar to the archaeal form III RubisCO, in some CPR bacteria from the Parcubacteria (OD1), WS6 and Microgenomates (OP11) phyla. In addition, we significantly expand the Peregrinibacteria (PER) II/III RubisCO diversity and report the first II/III RubisCO sequences from the Microgenomates and WS6 phyla. To provide a metabolic context for these RubisCOs, we reconstructed near-complete (>93%) PER genomes and the first closed genome for a WS6 bacterium, for which we propose the phylum name Dojkabacteria. Genomic and bioinformatic analyses suggest that the CPR RubisCOs function in a nucleoside pathway similar to that proposed in Archaea. Detection of form II/III RubisCO and nucleoside metabolism gene transcripts from a PER supports the operation of this pathway in situ. We demonstrate that the PER form II/III RubisCO is catalytically active, fixing CO2 to physiologically complement phototrophic growth in a bacterial photoautotrophic RubisCO deletion strain. We propose that the identification of these RubisCOs across a radiation of obligately fermentative, small-celled organisms hints at a widespread, simple metabolic platform in which ribose may be a prominent currency. PMID:27137126

  9. Extended radical mastectomy versus simple mastectomy followed by radiotherapy in primary breast cancer. A fifty-year follow-up to the Copenhagen Breast Cancer randomised study.

    PubMed

    Johansen, Helge; Kaae, Sigvard; Jensen, Maj-Britt; Mouridsen, Henning T

    2008-01-01

    From November 1951 to December 1957, 666 consecutive patients with untreated primary breast cancer admitted to the Radium Center in Copenhagen were randomised before their operability was evaluated into two groups, simple mastectomy with postoperative radiotherapy or extended radical mastectomy. Following physical examination 241 of the patients were excluded, primarily due to tumours deemed inoperable due to clinical criteria (n =107) and due to poor general condition (n =69). Twenty-five years results of disease-free free survival and fifty years results of survival are presented, showing no difference between the two groups. Patients with clinical stage I did significantly better than patients with stage II-III tumours. Patients with grade I tumours had a better survival than patients with grade II-III. The breast cancer associated mortality was lower in premenopausal patients compared to postmenopausal patients. An excess mortality due to breast cancer was evident up to 20-25 years following the primary diagnosis.

  10. General Aviation Avionics Statistics: 1977.

    DTIC Science & Technology

    1980-06-01

    UNCLASSIFIED TSC-FAA-80-13 FAA-MS-SO-6 NL IIIII."IIE -INEIlllllll 1111 Q 8 j11. 5 j III� 111112- IIIII 8 1111.25 H .II 4 jl 6 MICROCOPY...i t y_ ’ *rout . E - Radi ;Ct A t L I hi I Ir I IidI C C’,,V t I A \\ 1 ’ 1J A ’ III L’,. th\\ l II, Ad l l Q ,"C ) L’ it - t W I 11 t F I! L’ ia I I...Cq . P. N. *Vgw~ .-. P. C ~ e .- 4 C ** C w * . * * - C* N * C c C C g fF- In - * , CC * C; C 0 * P g P *g ’ e q . Fn N1 CN N1 VP N K) cc 4N T N u- a

  11. Hydrocarbon source potential of the Tanezzuft Formation, Murzuq Basin, south-west Libya: An organic geochemical approach

    NASA Astrophysics Data System (ADS)

    El Diasty, W. Sh.; El Beialy, S. Y.; Anwari, T. A.; Batten, D. J.

    2017-06-01

    A detailed organic geochemical study of 20 core and cuttings samples collected from the Silurian Tanezzuft Formation, Murzuq Basin, in the south-western part of Libya has demonstrated the advantages of pyrolysis geochemical methods for evaluating the source-rock potential of this geological unit. Rock-Eval pyrolysis results indicate a wide variation in source richness and quality. The basal Hot Shale samples proved to contain abundant immature to early mature kerogen type II/III (oil-gas prone) that had been deposited in a marine environment under terrigenous influence, implying good to excellent source rocks. Strata above the Hot Shale yielded a mixture of terrigenous and marine type III/II kerogen (gas-oil prone) at the same maturity level as the Hot Shale, indicating the presence of only poor to fair source rocks.

  12. Prevalence of canine methicillin resistant Staphylococcus pseudintermedius in a veterinary diagnostic laboratory in Italy.

    PubMed

    De Lucia, M; Moodley, A; Latronico, F; Giordano, A; Caldin, M; Fondati, A; Guardabassi, L

    2011-12-01

    The overall prevalence of methicillin-resistant Staphylococcus pseudintermedius (MRSP) was 2% (10/590) among 590 canine specimens submitted to an Italian veterinary diagnostic laboratory during a two-month period, and 21% (10/48) among Staphylococcus intermedius group (SIG) isolates. All methicillin-resistant strains exhibited additional resistance to fluoroquinolones, gentamicin, lincosamides, tetracyclines, and potentiated sulfonamides, belonged predominantly to spa type t02 and harboured SCCmec type II-III cassette.

  13. The Effects of Climatological and Transient Wind Forcing on Eddy Generation in the California Current System

    DTIC Science & Technology

    1989-09-01

    M.L. Batteen (408) 646- 2768 I 54Ss DD Form 1473, JUN 86 Prevous editions are obsolete SECURITY CLASS FICATION OF T’,S PAGE S/N 0102-LF-014-6603...34". .. ................. .. ’ " 2 T ISO - 250 .-- 192 36 ---------- - ----. - 32 -- --- ii~iii 326 64 4 532 440 564 520 2 2 3 44I -- 0 312 448 364 320

  14. Differential effect of dark rearing on long-term potentiation induced by layer IV and white matter stimulation in rat visual cortex.

    PubMed

    Salami, M; Fathollahi, Y; Semnanian, S; Atapour, N

    2000-12-01

    In the earlier work, we showed that primed-burst stimulation (PBs) is an effective protocol to induce long-term potentiation (LTP) in layer II/III of adult rat visual cortex in vitro. In the present study, we investigated effects of dark rearing on potentiation of layer II/III responses to stimulation of layer IV or the underlying white matter in the visual cortex in vitro. Long-term potentiation was induced by PBs applied to white matter or layer IV of the cortex in light and dark reared rats. Regardless of the stimulation site, layer II/III field potentials consisted of two components. In general, the latency of responses in dark reared rats was shorter than that in light reared ones. Whereas PBs of layer IV produced LTP of two components in both the groups, that of white matter induced an appreciable potentiation of the second component in both groups and the first component only in dark reared rats. These results indicate that PBs of either white matter or layer IV can gain access to the modifiable synapses that are related to the second component of layer II/III responses in light and dark reared visual cortex, but accessibility of the modifiable synapses that are related to first component depends on the tetanization site. The dark rearing enhances accessibility of the modifiable synapses that are related to the first component following PBs of the white matter. It is suggested that the immaturity of inhibitory circuits and/or better function of excitatory ones in the visual cortex of dark reared rats may contribute to the enhanced accessibility of the first component.

  15. Algorithmic Approximation of Optimal Value Differential Stability Bounds in Nonlinear Programming,

    DTIC Science & Technology

    1981-08-01

    NCLASSIFIED RANO/PA6659 N IN *~4 112.0.0 ~11111,.. I32 111 IIIII 111111.25 MICROCOPY RESOLUTION TESI CHART NATIOt AL BJRLAU Of SIANDARD 1964 A * LEVEL 00 o pm...Sensitivity Analysis in Parametric Nonlinear Programming, Doctoral Dissertation, School of Engineering and Applied Science, The George Washington University...Differential Stability of the Optimal Value Function in Constrained Nonlinear Programing, Doctoral Disser- tation, School of Engineering and Applied

  16. [Role of myocardial micropump function in the pathogenesis of ischemic heart disease].

    PubMed

    Feketa, V P

    1996-01-01

    Myocardial vibrational activity examined in 40 patients with functional classes II-III coronary heart disease and in 20 apparently healthy individuals, which indirectly reflects the status of its micropump function has been studied by using a spectral analysis of the first heart sound. Inhibition of the micropump function of the myocardium with its higher oxygen demands has been found to substantially contribute to the pathogenesis of myocardial ischemia.

  17. Spaceflight induces changes in the synaptic circuitry of the postnatal developing neocortex

    NASA Technical Reports Server (NTRS)

    DeFelipe, J.; Arellano, J. I.; Merchan-Perez, A.; Gonzalez-Albo, M. C.; Walton, K.; Llinas, R.

    2002-01-01

    The establishment of the adult pattern of neocortical circuitry depends on various intrinsic and extrinsic factors, whose modification during development can lead to alterations in cortical organization and function. We report the effect of 16 days of spaceflight [Neurolab mission; from postnatal day 14 (P14) to P30] on the neocortical representation of the hindlimb synaptic circuitry in rats. As a result, we show, for the first time, that development in microgravity leads to changes in the number and morphology of cortical synapses in a laminar-specific manner. In the layers II/III and Va, the synaptic cross-sectional lengths were significantly larger in flight animals than in ground control animals. Flight animals also showed significantly lower synaptic densities in layers II/III, IV and Va. The greatest difference was found in layer II/III, where there was a difference of 344 million synapses per mm(3) (15.6% decrease). Furthermore, after a 4 month period of re-adaptation to terrestrial gravity, some changes disappeared (i.e. the alterations were transient), while conversely, some new differences also appeared. For example, significant differences in synaptic density in layers II/III and Va after re-adaptation were no longer observed, whereas in layer IV the density of synapses increased notably in flight animals (a difference of 185 million synapses per mm(3) or 13.4%). In addition, all the changes observed only affected asymmetrical synapses, which are known to be excitatory. These results indicates that terrestrial gravity is a necessary environmental parameter for normal cortical synaptogenesis. These findings are fundamental in planning future long-term spaceflights.

  18. A Vertical Wind Angle Standard Deviation Calculation Method for the Unstable Surface Boundary Layer.

    DTIC Science & Technology

    1983-08-01

    UT C ILTOFT RUG 63 UNCLASSIFIED DPG-TR -3 41 F6 4/ 2L .41 L5.04 1111LA. 1 1112.0- 11111 .5 ~ ?"IIIII 111111. MICROCOPY RESOLUTION TEST CHART NATIONAL ...equation (16). R-Fg = F1 + Fh (16) Swinbank (1964) tabulated R and F data taken at an open field near Kerang, Australia under a variety of weater ...Addressee Copies Di rector 1 National Oceanic and Atmospheric Administration Environmental Research Laboratories Boulder, CO 80302 Cooperative

  19. An Annotated Bibliography of MANPRINT-Related Assessments and Evaluations Conducted by the U.S. Army, 2nd Edition: 1953 to 2009. Volume 3 - Test and Evaluation Reports

    DTIC Science & Technology

    2010-02-01

    Contermeasures Munitions (CMWS/AIRCMM) 2002 Aircraft- Fixed Wing - Cargo- C17 DRAS C17 DRAS C-17 Dual Row Airdrop System (DRAS) 2002 Aircraft- Fixed Wing - Cargo...JCA C-27 JCA C-27 Joint Cargo Aircraft (JCA) 2007 Aircraft- Fixed Wing - Intel- PROPHET PROPHET PROPHET Block II/III Acquisition Milestone (Phase...B) 2002 Aircraft- Fixed Wing - Intel- PROPHET Ground PROPHET Ground Prophet Ground. Block 1 2001 Aircraft- Helicopter- Aircrew- AW AW Air Warrior

  20. Unusual Presentation of Hydatid Cyst in Breast with Magnetic Resonance Imaging Findings

    PubMed Central

    Koc, Ali; Vurdem, Umit Erkan; Karabiyik, Ozgur; Gumus, Ummugulsum Ozgul

    2017-01-01

    We report a case of 59-year-old woman with a painful left breast mass, compatible with types II-III hydatid cyst. Lesion was evaluated with mammography, ultrasound, computed tomography, and magnetic resonance imaging modalities. Magnetic resonance imaging had important diagnostic role with demonstrating characteristic features of the lesion and had capability of showing complications. Surgery also confirmed the diagnosis of a hydatid cyst. PMID:28167966

  1. [Gastric esophagoplasty in cancer of the middle third of the esophagus].

    PubMed

    Mamontov, A S; Orokhovskiĭ, V I; Ivanov, P A; Vasilenko, L I

    1986-08-01

    The examination of 119 corpses, experiments in 67 dogs and clinical management of 127 patients with the II-III degrees of cancer of the middle third of the esophagus have supported new methods of esophagoplasty by a tube from the greater curvature of the stomach with highly germetic sutures, longer transplants and diaphragmo-percutaneous conduction of it onto the neck. The method is shown to be more safe, less traumatic, not followed by functional alterations of the heart, lungs, diaphragm.

  2. Mapping Emplaced Articulated Concrete Mattress Using Geoelectrical and Electromagnetic Techniques.

    DTIC Science & Technology

    1998-08-01

    2450 2200 1760 2800 2491 2378 1745 1823 2015 11 (mV/ft) +.0055 +.0500 +.0055 +.00618 +.0105 ÷.00832 +.08484 +.0070 4.01 HI (depth to source, ft) 115...Calculated value NIf ) >V E 0 _J < I Iw - MODEL, , 0-10 Line XMID Depth Current I no. (ft (ft) (mA/f’n1 2450 10O0 .0055 Is 1 -d-- iiiiI 2160 44.1

  3. Toward a New "New Triad"

    DTIC Science & Technology

    2009-04-01

    ii-iii. 50 Rumsfeld, ―Nuclear Posture Review Report: Forward.‖ 51 DOD, ―Findings of the Nuclear Posture Review,‖ 9. 52 Pilat , ―The end of the...28 Pilat , Joseph F. ―The end of the NPT regime?‖ International Affairs 83:3 (2007): 469-482. Raser, John R. ―Deterrence Research: Past

  4. Field Surveys, IOC Valleys. Volume III, Part II. Cultural Resources Survey, Pine and Wah Wah Valleys, Utah.

    DTIC Science & Technology

    1981-08-01

    including horse, camel, mammoth, Ertm E-TR-48-III-II 20 musk ox, and certain species of bison, goat, and bear, which had previously inhabited the marsh and...34 - - -9,$.. 𔄃 Im I I I Si to * Location lype/Contents Affiliation 42B@644 rid e over cr ek - P/J depression, cleared areas, Fr elon (f4-5-18-92) ground

  5. The Impact of Data Rates on the Design of a Fiber Optics Guidance System.

    DTIC Science & Technology

    1982-07-01

    function.5 A thorough study has been performed of the effects of video bandwidth, sensor resolution, sensor field of view, sensor video truncation...when fields of view greater than 1.8 degrees are used. Note also that video zoom levels need to be determined for target and artillery burst...recover the baseband signal. 7 j ii II__iii_,,_ The problem addressed by rate-distortion theory is the minimi- zation of channel-capacity requirement qhile

  6. Inhibition of TRPV1 channels enables long-term potentiation in the entorhinal cortex.

    PubMed

    Banke, Tue G

    2016-04-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is a non-selective cation channel that is mainly found in nociceptive neurons of the peripheral nervous system; however, these channels have also been located within the CNS, including the entorhinal cortex. Whole-cell patch-clamp recordings of principal entorhinal cortex (EC) layers II/III neurons revealed that evoked inhibitory postsynaptic currents were depressed by application of the TRPV1 agonist capsaicin (CAP), accompanied by a change in the pair-pulse ratio (PPR). In addition, recordings of miniature inhibitory postsynaptic currents (mIPSCs) revealed that inter-event intervals but not amplitude were decreased in wild-type (WT) after application of CAP. This suggests that TRPV1 channels are functional in the entorhinal cortex and are located on inhibitory neurons with their axonal arborization within layers II/III. In order to study TRPV1 channels and their involvement in long-term potentiation (LTP) induction in a more intact circuit, extracellular field potential recordings were performed in EC layers II/III. It was found that activated TRPV1 channels preclude induction of long-term potentiation. In sharp contrast, clear LTP was observed when antagonizing TRPV1 channels or recording from TRPV1 knock-out mice. Thus, these results suggests that signaling through activating inhibitory presynaptic TRPV1 channels represents a novel mechanism by which a shift in feed-forward inhibition of layers II/III cortical principal neurons prompt changes in synaptic strength and thereby contribute to a change of information storage within the brain.

  7. Downsizing Information Systems: Framing the Issues for the Office of Naval Intelligence (ONI)

    DTIC Science & Technology

    1994-03-01

    AD-A279 888lBr Ii AI IN itlt IIIII EllH NAVAL POSTGRADUATE SCHOOL Monterey, California SOTTO UN Q I’ý, . THESIS DOWNSIZING INFORMATION SYSTEMS...Master’s Thesis 4. TITLE AND SUBTITLE S. FUNDING NUMBERS DOWNSIZING INFORMATION SYSTEMS: FRAMING THE ISSUES FOR THE OFFICE OF NAVAL INTELLIGENCE (ONI...13. ABSTRACT (Maximum 200 words) Downsizing information systems from large and centralized mainframe computing architectures to smaller and

  8. Bd +60 73 = Igr J00370+6122

    NASA Astrophysics Data System (ADS)

    Negueruela, Ignacio; Reig, Pablo

    2004-05-01

    A classification spectrum of BD +60 73, reported to be the optical counterpart to IGR J00370+6122 (ATel #281), was taken on the night of 2003 July 7th with the 2.5-m Issac Newton telescope at La Palma. The derived spectral type is BN0.5II-III, where the composite luminosity class indicates an intermediate luminosity. The Nitrogen enhancement is moderately high, with numerous NII lines being rather stronger than corresponds to the spectral type.

  9. Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

    PubMed

    Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

    2015-08-01

    The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

  10. Plasma melatonin is reduced in Huntington's disease.

    PubMed

    Kalliolia, Eirini; Silajdžić, Edina; Nambron, Rajasree; Hill, Nathan R; Doshi, Anisha; Frost, Chris; Watt, Hilary; Hindmarsh, Peter; Björkqvist, Maria; Warner, Thomas T

    2014-10-01

    This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24-hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease.

  11. Statewide land cover derived from multiseasonal Landsat TM data: A retrospective of the WISCLAND project

    USGS Publications Warehouse

    Reese, H.M.; Lillesand, T.M.; Nagel, D.E.; Stewart, J.S.; Goldmann, R.A.; Simmons, T.E.; Chipman, J.W.; Tessar, P.A.

    2002-01-01

    Landsat Thematic Mapper (TM) data were the basis in production of a statewide land cover data set for Wisconsin, undertaken in partnership with U.S. Geological Survey's (USGS) Gap Analysis Program (GAP). The data set contained seven classes comparable to Anderson Level I and 24 classes comparable to Anderson Level II/III. Twelve scenes of dual-date TM data were processed with methods that included principal components analysis, stratification into spectrally consistent units, separate classification of upland, wetland, and urban areas, and a hybrid supervised/unsupervised classification called "guided clustering." The final data had overall accuracies of 94% for Anderson Level I upland classes, 77% for Level II/III upland classes, and 84% for Level II/III wetland classes. Classification accuracies for deciduous and coniferous forest were 95% and 93%, respectively, and forest species' overall accuracies ranged from 70% to 84%. Limited availability of acceptable imagery necessitated use of an early May date in a majority of scene pairs, perhaps contributing to lower accuracy for upland deciduous forest species. The mixed deciduous/coniferous forest class had the lowest accuracy, most likely due to distinctly classifying a purely mixed class. Mixed forest signatures containing oak were often confused with pure oak. Guided clustering was seen as an efficient classification method, especially at the tree species level, although its success relied in part on image dates, accurate ground troth, and some analyst intervention. ?? 2002 Elsevier Science Inc. All rights reserved.

  12. Layer I neurons of rat neocortex. I. Action potential and repetitive firing properties.

    PubMed

    Zhou, F M; Hablitz, J J

    1996-08-01

    1. Whole cell patch-clamp techniques, combined with direct visualization of neurons, were used to study action potential (AP) and repetitive firing properties of layer I neurons in slices of rat neocortex. 2. Layer I neurons had resting membrane potentials (RMP) of -59.8 +/- 4.7 mV (mean +/- SD) and input resistances (RN) of 592 +/- 284 M Omega. Layer II/III pyramidal neurons had RMPs and RNs of -61.5 +/- 5.6 mV and 320 +/- 113 M omega, respectively. A double exponential function was needed to describe the charging curves of both neuron types. In layer I neurons, tau(0) was 45 +/- 22 ms and tau(1) was 5 +/- 3.3 ms whereas in layer II/III pyramidal neurons, tau(0) was 41 +/- 11 ms and tau(1) was 3 +/- 2.6 ms. Estimates of specific membrane resistance (Rm) for layer I and layer II/III cells were 45 +/- 22 and 41 +/- 11 k omega cm2, respectively (Cm was assumed to be 1 microF/cm2). 3. AP threshold was -41 +/- 2 mV in layer I neurons. Spike amplitudes, measured from threshold to peak, were 90.6 +/- 7.7 mV. AP durations, measured both at the base and half maximal amplitude, were 2.5 +/- 0.4 and 1.1 +/- 0.2 ms, respectively. AP 10-90% rise and repolarization times were 0.6 +/- 0.1 and 1.1 +/- 0.2 ms, respectively. In layer II/III pyramidal neurons, AP threshold was -41 +/- 2.5 mV and spike amplitude was 97 +/- 9.7 mV. AP duration at base and half maximal amplitude was 5.4 +/- 1.1 ms and 1.8 +/- 0.2 ms, respectively. AP 10-90% rise and decay times were 0.6 +/- 0.1 ms and 2.8 +/- 0.6 ms, respectively. 4. Layer I neurons were fast spiking cells that showed little frequency adaptation, a large fast afterhyperpolarization (fAHP), and no slow afterhyperpolarization (sAHP). Some cells had a medium afterhyperpolarization (mAHP) and a slow afterdepolarization (sADP). All pyramidal cells in layer II/III and "atypical" pyramidal neurons in upper layer II showed regular spiking behavior, prominent frequency adaptation, and marked sAHPs. 5. In both layer I neurons and layer II/III

  13. DISTINCT COPY NUMBER ALTERATIONS AND INCIDENCE OF CHROMOTHRIPSIS ASSOCIATED WITH GRADE AND PROGNOSIS IN IDH MUTANT AND WILD-TYPE GLIOMAS

    PubMed Central

    Colman, Howard; Cohen, Adam; Aldape, Ken; Sato, Mariko; Mason, Clint; Diefes, Kristin; Heathcock, Lindsey; Abegglen, Lisa; Shrieve, Dennis; Couldwell, William; Schiffman, Joshua

    2014-01-01

    BACKGROUND: Both IDH mutated (IDHmut) and wild-type (IDHwt) lower grade gliomas can progress to GBM. However, a detailed study of alterations associated with progression of these molecularly distinct tumor types has not been described. Here we perform an analysis of copy number alterations (CNA) across all grades (Grade II-II and Grade IV) IDHmut vs IDHwt infiltrating gliomas. METHODS: DNA was extracted from 94 patient FFPE glioma samples from 4 clinical and molecular groups: Grade II-III IDHwt (n = 17), Grade II-III IDHmut (n = 28), Grade IV IDHwt (n = 25), and Grade IV IDHmut (n = 24). CNA were detected by molecular inversion probes (OncoScan FFPE Express, Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). GISTIC was used to define deletions and amplifications. Chromothripsis (“chromosomal shattering”) was defined using stringent criteria of at least ten switches of CNA in individual chromosomes. RESULTS: Unsupervised clustering of CNAs demonstrated distinct clusters within IDHmut gliomas that correlated with grade. However, within IDHwt gliomas all grades clustered together regardless of grade, with Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN) seen in most tumors. IDHwt Grade II-III and Grade IV tumors both displayed relatively poor prognosis (median survivals of 65.4 and 37.4 weeks). However, IDHmut gliomas had better survival for all grades (604.3 weeks for Grade II-III and 270.3 weeks for Grade IV). Grade IV IDHmut gliomas were more likely to have gains of 1q25.3 (SMG7, NCF2), 1q32.1 (KIF14, DDX59, BTG2), 6p21.1 (HSP90AB1 and other genes) and loss of 3p21 compared with Grade II-III. Functional analyses showed that IDHwt tumors had more amplifications in receptor tyrosine kinases and their downstream pathways. In terms of novel prognostic markers within IDHmut Grade II-III tumors, multivariate analysis identified loss of estrogen receptor B and loss of 10q26.3 containing part of GLRX3 as poor prognostic

  14. Cell-cycle and suppressor proteins expression in uterine cervix in HIV/HPV co-infection: comparative study by tissue micro-array (TMA)

    PubMed Central

    Nicol, Alcina F; Pires, Andréa Rodrigues Cordovil; de Souza, Simone R; Nuovo, Gerard J; Grinsztejn, Beatriz; Tristão, Aparecida; Russomano, Fabio B; Velasque, Luciane; e Silva, José R Lapa; Pirmez, Claude

    2008-01-01

    Background The oncoproteins of human papillomavirus (HPVs) directly effect cell-cycle control. We hypothesize that regulatory and cell cycle protein expression might be additionally modified in the cervix of HIV/HPV co-infected women. Methods We analyzed the expression of Rb, p27, VEGF and Elf-1 transcriptor factor by immunohistochemistry in 163 paraffin-embeded cervical samples using Tissue Micro-Array (TMA) and correlated this to HIV-1 and HPV infection. Results HIV/HPV co-infection was associated with a significant increase in expression (p < 0.001) of VEGF and p27 in both low and high grade CIN when compared to the cervices of women infected by HPV alone. Decreased Rb expression was evident with increased CIN grade in the cervices of women infected with HPV alone (p = 0.003 average of cells/mm2 in CIN I: 17.9, CIN II/III: 4.8, and tumor 3.9). Rb expression increased 3-fold for both low and high grade CIN with HPV/HIV-1 co-infection compared to HPV infection alone but did not reach statistical significance. There was a significant increase in Elf-1 expression in HPV+/HIV- women with CIN II/III and tumor (average of cells/mm2 in CIN I: 63.8; CIN II/III: 115.7 and tumor: 112.0, p = 0.005), in comparison to controls. Conclusion Co-infection of HPV and HIV leads to significant increase in the VEGF and p27 expression when compared to HPV+/HIV-negative infection that could facilitate viral persistence and invasive tumor development. PMID:18840277

  15. EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer

    PubMed Central

    Blayney, Jaine K.; McArt, Darragh G.; Redmond, Keara L.; Weir, Jessica-Anne; Bradley, Conor A.; Sasazuki, Takehiko; Shirasawa, Senji; Wang, Tingting; Srivastava, Supriya; Ong, Chee Wee; Arthur, Ken; Salto-Tellez, Manuel; Wilson, Richard H.

    2015-01-01

    Purpose EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumour initiation, neo-vascularization and metastasis in a wide range of epithelial and mesenchymal cancers, however its role in colorectal cancer (CRC) recurrence and progression is unclear. Experimental Design EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumours (N=338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive CRC cell line models. Results Colorectal tumours displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III CRC tissues, in both univariate and multivariate analyses. Pre-clinically, we found that EphA2 was highly expressed in KRASMT CRC cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines and down-regulation of EphA2 using RNAi or recombinant EFNA1, suppressed migration and invasion of KRASMT CRC cells. Conclusions These data show that EpHA2 is a poor prognostic marker in stage II/III CRC, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. PMID:26283684

  16. Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex.

    PubMed

    Dixit, Rajiv; Wilkinson, Grey; Cancino, Gonzalo I; Shaker, Tarek; Adnani, Lata; Li, Saiqun; Dennis, Daniel; Kurrasch, Deborah; Chan, Jennifer A; Olson, Eric C; Kaplan, David R; Zimmer, Céline; Schuurmans, Carol

    2014-01-08

    The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genes Neurog1 and Neurog2 are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex. Using loss-of-function and gain-of-function approaches, we find that Neurog1 has a unique early role in reducing CR cell neurogenesis by tempering Neurog2's proneural activity. In addition, Neurog1 and Neurog2 have redundant functions in the ventral pallium, acting in two phases to first specify a CR cell fate and later to specify layer II/III piriform cortex neuronal identities. In the early phase, Neurog1 and Neurog2 are also required for lot cell differentiation, which we reveal are a subset of CR neurons, the loss of which prevents mitral cell axon innervation and LOT formation. Consequently, mutation of Trp73, a CR-specific cortical gene, results in lot cell and LOT axon displacement. Neurog1 and Neurog2 thus have unique and redundant functions in the piriform cortex, controlling the timing of differentiation of early-born CR/lot cells and specifying the identities of later-born layer II/III neurons.

  17. Efficacy of Rotigotine at Different Stages of Parkinson’s Disease Symptom Severity and Disability: A Post Hoc Analysis According to Baseline Hoehn and Yahr Stage

    PubMed Central

    Giladi, Nir; Nicholas, Anthony P.; Asgharnejad, Mahnaz; Dohin, Elisabeth; Woltering, Franz; Bauer, Lars; Poewe, Werner

    2016-01-01

    Background: The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in ‘off’ state) Parkinson’s disease (PD). Objective: To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. Methods: Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. Results: Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p < 0.05 for each HY stage), with treatment differences increasing with increasing HY stages. Similar results were observed for UPDRS II and UPDRS III. Conclusions: This post hoc analysis suggests that rotigotine may be efficacious across a broad range of progressive stages of PD symptom severity and functional disability (HY stages 1–4). PMID:27567886

  18. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology

    PubMed Central

    2016-01-01

    Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis. PMID:26595189

  19. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology.

    PubMed

    Di Jeso, Bruno; Arvan, Peter

    2016-02-01

    Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis.

  20. De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer

    PubMed Central

    2012-01-01

    Background MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome. Methods The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers. Results More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients. Conclusions Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications. PMID:22400902

  1. Development and Evaluation of Adeno HTLV-III Hybrid Virus and Non- Cytopathic HTLV-III Mutant for Vaccine Use

    DTIC Science & Technology

    1990-02-06

    PTIf 7IL E COPY AD_ _ _ DIVELOPMENT AND EVALUATION OF Ln ADENO HTLV -1II HYBRID VIRUS AND NON-CYTOPATHIC HTLV -III MUTANT FOR VACCINE USE " DTIC IIIII...Development and Evaluation of Adeno- HTLV -III Hybrid Virus and Non-Cytopathic HTLV -III Mutant for Vaccine Use 12. PERSONAL AUTHOR(S) Dusing, Sandra K...reduction in OKT4+ cells. Minor cutaneous infections, diarrhea, weight loss and fever may be associated with ARC (8). Two subtypes of virus have been

  2. Photochemical properties of Yt base in aqueous solution.

    PubMed Central

    Paszyc, S; Rafalska, M

    1979-01-01

    Photoreactivity of Yt base [I] has been studied in aqueous solution [pH approximately 6] saturated with oxygen. Two photoproducts (II,III], resulting from irradiation at lambda = 253.7 nm and lambda greater than or equal to 290 nm, were isolated and their structures determined. The quantum yield for Yt base disappearance [zeta dis] is 0.002 [lambda = 313 nm]. It was shown that dye-sensitized photooxidation of Yt base in aqueous solution occurs according to a Type I mechanism, as well as with participation of singlet state oxygen. Quantum yields, fluorescence decay times and phosphorescence of Yt base have been also determined. PMID:424298

  3. Raman spectra of solid benzene under high pressure

    NASA Technical Reports Server (NTRS)

    Thiery, M.-M.; Kobashi, K.; Spain, I. L.

    1985-01-01

    Raman spectra of solid benzene have been measured at room temperature up to about 140 kbar, using the diamond anvil cell. Effort has been focused upon the lattice vibration spectra at pressures above that of phase II. It is found that a change in slopes occurs in the frequency-pressure curves at about 40 kbar. Furthermore, a new band appears above 90 kbar. These features probably correspond respectively to the II-III phase transition, which has been reported previously, and a III-IV phase transition, reported here for the first time.

  4. Regional but fatal: Intraperitoneal metastasis in gastric cancer

    PubMed Central

    Wei, Jia; Wu, Nan-Die; Liu, Bao-Rui

    2016-01-01

    Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients. PMID:27672270

  5. Representing and Reasoning about Change in Geologic Interpretation.

    DTIC Science & Technology

    1983-12-01

    LAB R 6 SIMMONS DEC 83 UNCLASSIFIED AIl-TR-749 NGO014-80- C -9505 F/G 8/7 N ILEhhh hmmlEhmm hmhmhhhum o - IIII IIIIII 1__ _ _ 11 32-- IIIII ’ 2 MICROCOPY...NYS C T L G UM E AI-TR-749 7-ś_-_.’-0 4. TITLE (end Subtitle) S. TYPE OF REPORT & PERIOD COVERED Representing and Reasoning About Change in Technical...report Geologic Interpretation S. PERFORMING ONG. REPORT NUMBER 7. AuTmOR(m) S. CONTRACT OR GRANT NUMBER(e) Reid Gordon Simmons N00014-80- C -0505 9

  6. Implementing the UCSD PASCAL system on the MODCOMP computer. [deep space network

    NASA Technical Reports Server (NTRS)

    Wolfe, T.

    1980-01-01

    The implementation of an interactive software development system (UCSD PASCAL) on the MODCOMP computer is discussed. The development of an interpreter for the MODCOMP II and the MODCOMP IV computers, written in MODCOMP II assembly language, is described. The complete Pascal programming system was run successfully on a MODCOMP II and MODCOMP IV under both the MAX II/III and MAX IV operating systems. The source code for an 8080 microcomputer version of the interpreter was used as the design for the MODCOMP interpreter. A mapping of the functions within the 8080 interpreter into MODCOMP II assembly language was the method used to code the interpreter.

  7. Valvular dysplasia and congestive heart failure in a juvenile African penguin (Spheniscus demersus).

    PubMed

    McNaughton, Allyson; Frasca, Salvatore; Mishra, Neha; Tuttle, Allison D

    2014-12-01

    Abstract: An aquarium-housed, 6-mo-old African penguin (Spheniscus demersus) presented with acute respiratory distress. Auscultation revealed a grade II-III systolic murmur in the absence of adventitial sounds, and an enlarged heart without pulmonary edema was seen radiographically. Echocardiographic evaluation revealed atrioventricular (AV) valvular dysplasia and ventricular enlargement. The penguin was treated with enalapril, furosemide, and pimobendan but died within 3 wk of detection of the murmur. Congenital dysplasia of the right AV valve with right atrial and ventricular dilation and ventricular hypertrophy were diagnosed on postmortem examination.

  8. Marine Corps Combat Readiness Evaluation System. Software Applications (MCCRESSA) Subroutine Library.

    DTIC Science & Technology

    1985-08-01

    SCIE W E CAVESIUNCLASSIFIED AUG 85 GWU/IMSE/SERIAL-T-58i/85 F/G 9/2 UL EEEEEEEEEEEEEE EEEEEEEEEEEEEE EEEEEIIIIEEE 32 I:.0 11,1.I I I IIIIi I ~~~Ill...J . ; - - - - t [ " ’ "" " " " " " " " "" " " T-501 CNTSEL 4. CNTSEL 4.1. Description: Tr. Z2KJ sjbroitine wiA.: builc a crCoC refe- ence table

  9. Transcatheter Embolization of a Renal Artery Aneurysm Using Ethylene Vinyl Alcohol Copolymer

    SciTech Connect

    Rautio, Riitta Haapanen, Arto

    2007-04-15

    Our aim was to treat a clinically silent renal artery aneurysm. The patient was a 76-year-old man with elevated prostate-specific antigen and prostata biopsies with a gradus II-III adenocarcinoma who was incidentally found to have an aneurysm in his right renal artery. We performed a successful transcatheter embolization of the aneurysm using ethylene vinyl alcohol copolymer (Onyx). To avoid migration of the liquid material into the parent artery, a balloon was inflated in the orifice of the neck of the aneurysm while the liquid was injected. Five-month follow-up computed tomography (CT) imaging confirmed total occlusion of the aneurysm.

  10. Specification and Design Methodologies for High-Speed Fault-Tolerant Array Algorithms and Structures for VLSI.

    DTIC Science & Technology

    1987-06-01

    A182 772 SPECIFICATION AND DESIGN METHODOLOGIES FOR NIGH-SPEED 11 FAULT-TOLERANT ARRA.. CU) CALIFORNIA UNIY LOS ANGELES DEPT OF COMPUTER SCIENCE M D ...ERCEGOVAC ET AL. JUN 0? UNLASSIFIED N611-03--K-S49 F/ 91 ML Ji 1 2. ~ iiii -i ’IfIhIN I_______ IIIII .l n. ’ 3 ’ 3 .3 .5 *. .. w w, - .. .J’. ~ d ...STRUCTURES FOR VLSI Office of Naval Research Contract No. N00014-83-K-0493 Principal Investigator Milo D . Ercegovac ELECTE Co-Principal Ivestigator S AUG 0

  11. The ONR Workshop on Discrete Structures in Classification, May 5-6, 1992: Proceedings

    DTIC Science & Technology

    1992-05-01

    Discrete Mathematics to inform each other and their Scientific Officer of their current research activities. The second was for the PIs and Navy scientists...McMorris, University of Louisville Marc J. Lipman, Office of Naval Research GRANT: N00014-92-J-1574 R&T: 4111066---01 92-17140 92 6 " IIINhImIIIII... research relevant to Navy needs. Thus it had two goals. The first was for the Principal Investigators currently funded by ONR in this core area of

  12. Historical and Architectural Study of Buildings and Artifacts Associated with the Bulltown Historic Area, Burnsville Lake Project, Braxton County, West Virginia,

    DTIC Science & Technology

    1979-09-01

    whether Bryne or anybody else had previously operated a tannery at the site. Byrne owned large parcels of land in the area, but no structures or...8217 0) -I ILl 0 a U ~1iiiiiI~ - .1 a 0) F𔃾 a j 91 [Cj z X IŘ 92 Currently, roam 1 is the living room, roam 5 is the kitchen, room 6 is the dining rom...roof covered with corrugated sheet metal, and a four board backward Z batten door. For light, toward the front of the toilet, on oppostesides, two

  13. Persanura hyrcanica, a new genus and species of Neanurinae (Collembola: Neanuridae) from Iran, with a key to genera of the tribe Neanurini.

    PubMed

    Mayvan, Mahmood Mehrafroz; Shayanmehr, Masoumeh; Smolis, Adrian; Skarżyński, Dariusz

    2015-02-13

    Persanura hyrcanica, a new genus and species of Neanurini from Iran is described and illustrated. It has a unique suite of morphological characters: labrum with only 4 chaetae, fusion of tubercles So and L on head, tubercle Di on th. II-III with 2 chaetae and separation of tubercles Di on abd. V. The erected genus is closely related to Neanura MacGillivray, 1893, Kalanura Smolis, 2007 and Xylanura Smolis, 2011. An updated key to genera of the tribe Neanurini is given.

  14. Fitness and Activity Assessments among U.S. Army Populations: Implications for NCHS General Population Surveys,

    DTIC Science & Technology

    1986-01-01

    MR J A VOGEL JAN 86 7 CLAIFUAIEDUSARi EM-Mii’ F/G 6/14 N llQI *s. L. - III IIIII llL. " MICROCOPY RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS...WORDS (Continue on reverse aide If necory and identify by block number) Army Physical Fitness Test (APFT), Aerobic power, Muscular strength 20. Ain6...the specific test events, standards, applicable population and frequency have varied over the years. Prior to 1980 a five event fitness test was

  15. Social and Economic Impacts of Selected Potential Dredged Material Containment Facilities in Long Island Sound.

    DTIC Science & Technology

    1981-09-01

    DREDGING/DISPOSAL PERMlITS Pt/TaIm/Cfty pemitI~ ~ Suft. Aaajaav S . rtf M~l M9?3 0 Rover I". -I IlS to1 e~ cftI1 for ____ bwimimd. 196 10182 of Tida w~et...NORTHRDP SEP RI UNCLASSIFED CEM _4280-0OR735 DACW33-AG0-C 61 F/ S 13/2 NL .EIIIIIIIIIIIl EIIIIIIIIIIIIl IIfhhffffflllf L3= L2 11111 1. I iiiii 18...8217AGE ("oen Date &.**d) READ INSTRUCTIONSREPORT DOCU AENTATION PAGE BEFORE COMPLETING FORM 1. REPORT NUMBER z.OT ACCESSION No . Ot TS CATALOG NUMISER S

  16. Interface Specifications for SCR (Software Cost Reduction) (A-7E) Extended Computer Module. Revised.

    DTIC Science & Technology

    1984-12-31

    DC D L PRRNAS ET AL. |BIIE3E4L-2V62 mhmhhhhhhhhmmu mmhhhhhhhhhhhl EhhlllllllIIhl mIIIIIIIIIIIIII 1 .’ II 111NMI -7 11112. - IIII1.8 IIIII125 11111...CLASiiFIED ’a;E "A7 DN A-Oi 3 DISTRIBUTION AVAiLA8I~lTY OF REPORT ’ D DECASS; CA’ ON DOWNGRADING SC.IEOUIE Approved for public release; distribution...IDENTIFICATION %UMBER ORGANIZATION (if applicable ) Naval Electronic Systems Command Code 613 ______________________ Sc ADORE SS (City. State, and ZIP Code) 10

  17. VizieR Online Data Catalog: Teff against colours calibrations (Huang+, 2015)

    NASA Astrophysics Data System (ADS)

    Huang, Y.; Liu, X.-W.; Yuan, H.-B.; Xiang, M.-S.; Chen, B.-Q.; Zhang, H.-W.

    2016-07-01

    Based on nearly two hundred dwarf (luminosity classes: IV/V) and giant (luminosity classes: II/III) stars with direct effective temperature measurements of better than 2.5 per cent collected from the literature, we have derived metallicity-dependent Teff-colour relations in twenty-one colours for dwarfs and eighteen colours for giants in four photometric systems (the Johnson, Cousins, SDSS and 2MASS). The compiled data of dwarf and giant sample stars employed in the current work is presented. (1 data file).

  18. Electrooptic Crystal Growth and Properties

    DTIC Science & Technology

    1994-02-04

    the Applications of Ferroelectnics. ISAF 󈨠, Greenville, SC, 374 (1993). 9. A . M . Gadalla , Texas A & M University, unpublished results (1991). 10. B. D...TEES) for this work; Grant no. NAGW- 1194. We express our sincere thanks to Dr. A . M . Gadalla for the DTA and TGA expreiments. We also express our...AD-A276 023 *Texs Eginerin Exprimnt Satin Th Teas AM U Ivers I ity IIIII !11111 IilI li "*Texas Engineering Experiment Station The Texas A & M

  19. Recovery Following Orthognathic Surgery

    DTIC Science & Technology

    1993-01-01

    AD-A267 PAGE Form Approved IJIIIJi PAGEll IIIIiBlll0MB No. 0204-0 US ONL (LWv bl0nk 2.; REjR DATE t0, P .• ~ ~ ~ ~ ~ ~ 1 ’o M"• >’lr.n , . mll.r ,t9 co...SPONSORING/ MONITORING DEPARTMENT OF THE AIR FORCE AGENCY REPORT NUMBER 2 P TIC WRIGHT-PATTERSON AFB OH 45433-7765 _E L ,bCTE- 11. SUPPLEMENTARY NOTES 12a...DISTRIBUTION ’ AVAILABILITY STATEMENT I12b. DISTRIBUTION CODE Approved for Public Release IAW 190-1 Distribution Unlimited MICHAEL M. BRICKER, SMSgt

  20. Embankment Criteria and Performance Report, Missouri River, Fort Peck Lake, Montana. Volume I. Text Appendix A, Appendix B.

    DTIC Science & Technology

    1982-09-01

    lt I i I I . .. . . . , . . . . . . TABULATION AND I ,. L RF DR =2. MLE LM P R 1MMAIOM IM=IGATIONS P0R F0N PECK DAM - Contd Peld . ;% Role Book ’ook...I EllIhlllIhl!Il EIIIIIIIIIiil IIIIIIIEEIIIIE IIIIIIIE--EEI 11111j8 13 2 L11L11 2.2IIIIII 1111.25 IlI41. 6IIIII l llt IIl’ MICROCOPY RESOLUTION...AM, MNTAN EMBANKENT CITERI AND PEFORMACE REORT PAT1 son& I IS L ’It K,4 FORT T0 -, DA.MOTN WflAtiK*f NT* CRTE IAN t-i RMNEREOTPLT -- - - --- FORT PECK

  1. [Post-radiotherapy complications in malignant tumors of the nasopharynx. Analysis of 141 cases].

    PubMed

    Pastore, G; Krengli, M; Gambaro, G; Turri, L; Pisani, P

    1990-10-01

    This study was aimed at retrospectively analyzing the incidence and severity of the complications occurred in 141 patients affected with nasopharyngeal carcinomas treated with exclusive radiotherapy from 1960 to 1986. The acute complications were analyzed (85/141 grade II-III mucositis which generally came to a complete remission) which occurred during and immediately after radiation treatment. The late damage was then studied which occurred in 74/141 patients (52.5%) and which may worsen patients' quality of life. Finally, the incidence and severity of damage were correlated with some parameters: sex, age, performance status, risk factors (tabagism, alcoholism, diabetes), stage, total dose, fractionation, and processing techniques for treatment planning.

  2. CpG and TpA frequencies in the plant system.

    PubMed Central

    Boudraa, M; Perrin, P

    1987-01-01

    Higher plant nuclear sequences reveal avoidance of CpG and TpA doublets. Chloroplast sequences avoid the TpA doublet in all codon positions. The chloroplast genome is not methylated but codon positions II-III and untranslated regions avoid CpG. The mitochondrial genome, also unmethylated, avoids CpG in all codon positions. We therefore deduce that methylation is not sufficient to explain CpG avoidance in the higher plant systems. Other factors must be taken into account such as amino acid composition, codon choices and perhaps stability of the DNA helix. PMID:3497385

  3. Methamphetamine-induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite.

    PubMed

    Brown, Jeffrey M; Quinton, Maria S; Yamamoto, Bryan K

    2005-10-01

    High-dose methamphetamine (METH) is associated with long-term deficits in dopaminergic systems. Although the mechanism(s) which contributes to these deficits is not known, glutamate and peroxynitrite are likely to play a role. These factors are hypothesized to inhibit mitochondrial function, increasing the free radical burden and decreasing neuronal energy supplies. Previous studies suggest a role for the mitochondrial electron transport chain (ETC) in mediating toxicity of METH. The purpose of the present studies was to determine whether METH administration selectively inhibits complex II of the ETC in rats. High-dose METH administration (10 mg/kg every 2 h x 4) rapidly (within 1 h) decreased complex II (succinate dehydrogenase) activity by approximately 20-30%. In addition, decreased activity of complex II-III, but not complex I-III, of the mitochondrial ETC was also observed 24 h after METH. This inhibition was not due to direct inhibition by METH or METH-induced hyperthermia and was specific to striatal brain regions. METH-induced decreases in complex II-III were prevented by MK-801 and the peroxynitrite scavenger 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5-sulphonatophenyl) porphinato iron III. These findings provide the first evidence that METH administration, via glutamate receptor activation and peroxynitrite formation, selectively alters a specific site of the ETC.

  4. A call for more transparency of registered clinical trials on endometriosis

    PubMed Central

    Guo, Sun-Wei; Hummelshoj, Lone; Olive, David L.; Bulun, Serdar E.; D'Hooghe, Thomas M.; Evers, Johannes L.H.

    2009-01-01

    In response to the pressing need for more efficacious and safer therapeutics for endometriosis, there have been numerous reports in the last decade of positive results from animal and in vitro studies of various compounds as potential therapeutics for endometriosis. A handful of these have undergone phase II/III clinical trials. Since the announcement of the International Committee of Medical Journal Editors that mandated registration as a prerequisite for publication, 57 endometriosis-related clinical trials have been registered at ClinicalTrials.gov, an Internet-based public depository for information on drug studies. Among them, 25 are listed as completed, and 2 as suspended. There are 15 completed phase II/III trials, which evaluated the efficacy of various promising compounds. Yet only three of the 15 trials (20%) have published their results. The remaining 12 (80%) studies so far have not published their findings. We argue that this apparent lack of transparency will actually not benefit the trial sponsors or the public, and will ultimately prove detrimental to research efforts attempting to develop more efficacious and safer therapeutics for endometriosis. Thus we call for more transparency of clinical trials on endometriosis. PMID:19264712

  5. Heterotopic Transcallosal Projections Are Present throughout the Mouse Cortex

    PubMed Central

    Chovsepian, Alexandra; Empl, Laura; Correa, Daphne; Bareyre, Florence M.

    2017-01-01

    Transcallosal projection neurons are a population of pyramidal excitatory neurons located in layers II/III and to a lesser extent layer V of the cortex. Their axons form the corpus callosum thereby providing an inter-hemispheric connection in the brain. While transcallosal projection neurons have been described in some detail before, it is so far unclear whether they are uniformly organized throughout the cortex or whether different functional regions of the cortex contain distinct adaptations of their transcallosal connectivity. To address this question, we have therefore conducted a systematic analysis of transcallosal projection neurons and their axons across six distinct stereotactic coordinates in the mouse cortex that cover different areas of the motor and somatosensory cortices. Using anterograde and retrograde tracing techniques, we found that in agreement with previous studies, most of the transcallosal projections show a precise homotopic organization. The somata of these neurons are predominantly located in layer II/III and layer V but notably smaller numbers of these cells are also found in layer IV and layer VI. In addition, regional differences in the distribution of their somata and the precision of their projections exist indicating that while transcallosal neurons show a uniform organization throughout the mouse cortex, there is a sizeable fraction of these connections that are heterotopic. Our study thus provides a comprehensive characterization of transcallosal connectivity in different cortical areas that can serve as the basis for further investigations of the establishment of inter-hemispheric projections in development and their alterations in disease. PMID:28270750

  6. Colles' fracture treated with non-bridging external fixation: a 1-year follow-up.

    PubMed

    Andersen, J K; Høgh, A; Gantov, J; Vaesel, M T; Hansen, T Baek

    2009-08-01

    The results in 75 of 105 patients with Older type II/III (AO type A2.2, A3.1, A3.2) Colles' fractures, treated with non-bridging external fixation are presented. The mean age was 67.8 years, and all patients were followed prospectively for 12 months with radiological and functional assessment. No statistically significant loss of radial length, angulation or inclination was seen between the postoperative reduction and the 1-year follow-up examination. The clinical results after 1 year were 66 (88%) excellent/good, nine (12%) fair and 0 (0%) poor according to the modified Gartland and Werley score. Mean visual analogue scale pain score after 1 year was 0.8. In three patients (4%), re-displacement of the fracture occurred and was treated with plating. Non-bridging external fixation offers a reliable method of maintaining radiological reduction of Older type II/III fractures of the distal radius and gives a good functional outcome after 1 year.

  7. Layer-specific optogenetic activation of pyramidal neurons causes beta–gamma entrainment of neonatal networks

    PubMed Central

    Bitzenhofer, Sebastian H; Ahlbeck, Joachim; Wolff, Amy; Wiegert, J. Simon; Gee, Christine E.; Oertner, Thomas G.; Hanganu-Opatz, Ileana L.

    2017-01-01

    Coordinated activity patterns in the developing brain may contribute to the wiring of neuronal circuits underlying future behavioural requirements. However, causal evidence for this hypothesis has been difficult to obtain owing to the absence of tools for selective manipulation of oscillations during early development. We established a protocol that combines optogenetics with electrophysiological recordings from neonatal mice in vivo to elucidate the substrate of early network oscillations in the prefrontal cortex. We show that light-induced activation of layer II/III pyramidal neurons that are transfected by in utero electroporation with a high-efficiency channelrhodopsin drives frequency-specific spiking and boosts network oscillations within beta–gamma frequency range. By contrast, activation of layer V/VI pyramidal neurons causes nonspecific network activation. Thus, entrainment of neonatal prefrontal networks in fast rhythms relies on the activation of layer II/III pyramidal neurons. This approach used here may be useful for further interrogation of developing circuits, and their behavioural readout. PMID:28216627

  8. Neonatal sensory deprivation and the development of cortical function: unilateral and bilateral sensory deprivation result in different functional outcomes.

    PubMed

    Popescu, Maria V; Ebner, Ford F

    2010-07-01

    The normal development of sensory perception in mammals depends on appropriate sensory experience between birth and maturity. Numerous reports have shown that trimming some or all of the large mystacial vibrissa (whiskers) on one side of the face after birth has a detrimental effect on the maturation of cortical function. The objective of the present study was to understand the differences that occur after unilateral whisker trimming compared with those that occur after bilateral deprivation. Physiological deficits produced by bilateral trimming (BD) of all whiskers for 2 mo after birth were compared with the deficits produced by unilateral trimming (UD) for the same period of time using extracellular recording under urethan anesthesia from single cells in rat barrel cortex. Fast spiking (FSUs) and regular spiking (RSUs) units were separated and their properties compared in four subregions identified by histological reconstructions of the electrode penetrations, namely: layer IV barrel and septum, and layers II/III above a barrel and above a septum. UD upregulated responses in layer IV septa and in layers II/III above septa and perturbed the timing of responses to whisker stimuli. After BD, nearly all responses were decreased, and poststimulus latencies were increased. Circuit changes are proposed as an argument for how inputs arising from the spared whiskers project to the undeprived cortex and, via commissural fibers, could upregulate septal responses after UD. Following BD, more global neural deficits create a signature difference in the outcome of UD and BD in rat barrel cortex.

  9. Immunocytochemical localization of calcium-binding proteins, calbindin D28K-, calretinin-, and parvalbumin-containing neurons in the dog visual cortex.

    PubMed

    Yu, Song-Hee; Lee, Jea-Young; Jeon, Chang-Jin

    2011-09-01

    Although the dog is widely used to analyze the function of the brain, it is not known whether the distribution of calcium-binding proteins reflects a specific pattern in the visual cortex. The distribution of neurons containing calcium-binding proteins, calbindin D28K, calretinin, and parvalbumin in adult dog visual cortex were studied using immunocytochemistry. We also compared this labeling to that of gamma-aminobutyric acid (GABA). Calbindin D28K-immunoreactive (IR) neurons were predominantly located in layer II/III. Calretinin- and parvalbumin-IR neurons were located throughout the layers with the highest density in layers II/III and IV. The large majority of calbindin D28K-IR neurons were multipolar stellate cells. The majority of the calretinin-IR neurons were vertical fusiform cells with long processes traveling perpendicular to the pial surface. And the large majority of parvalbumin-IR neurons were multipolar stellate and round/oval cells. More than 90% of the calretinin- and parvalbumin-IR neurons were double-labeled with GABA, while approximately 66% of the calbindin D28K-IR neurons contained GABA. This study elucidates the neurochemical structure of calcium-binding proteins. These data will be informative in appreciating the functional significance of different laminar distributions of calcium-binding proteins between species and the differential vulnerability of calcium-binding proteins-containing neurons, with regard to calcium-dependent excitotoxic procedures.

  10. Association between obesity and prescribed medication use in England.

    PubMed

    Kinge, Jonas Minet; Morris, Stephen

    2014-12-01

    We investigate the association between obesity and use of prescribed medications in England. Data were taken from fourteen rounds of the Health Survey for England (1999-2012), which has measures of current prescribed medication use based on therapeutic classifications in the British National Formulary, and nurse-measured height and weight. We find that obesity has a statistically significant and positive association with use of a range of medicines for managing diseases associated with obesity. The mean probability of using any type of medication is 0.40 in those of normal weight, 0.44 in the overweight, 0.52 in obesity class I and 0.60 in obesity class II/III. Significant positive associations were found between obesity and the use of medication for diseases of the cardiovascular system, gastrointestinal system, respiratory system, and central nervous system, as well as for infections, endocrine system disorders, gynaecological/urinary disorders and musculoskeletal and joint disorders. Use of anti-obesity medication is low, even among those with class II/III obesity.

  11. Cellular and Molecular Basis for Stress-Induced Depression

    PubMed Central

    Seo, Ji-Seon; Wei, Jing; Qin, Luye; Kim, Yong; Yan, Zhen

    2016-01-01

    Chronic stress plays a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses. PMID:27457815

  12. Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus.

    PubMed

    Helmeke, C; Seidel, K; Poeggel, G; Bredy, T W; Abraham, A; Braun, K

    2009-10-20

    The aim of this study in the biparental rodent Octodon degus was to assess the impact of paternal deprivation on neuronal and synaptic development in the orbitofrontal cortex, a prefrontal region which is essential for emotional and cognitive function. On the behavioral level the quantitative comparison of parental behaviors in biparental and single-mother families revealed that (i) degu fathers significantly participate in parental care and (ii) single-mothers do not increase their maternal care to compensate the lack of paternal care. On the brain structural level we show in three-week-old father-deprived animals that layer II/III pyramidal neurons in the orbitofrontal cortex displayed significantly lower spine densities on apical and basal dendrites. Whereas biparentally raised animals have reached adult spine density values at postnatal day 21, fatherless animals seem "to catch up" by a delayed increase of spine density until reaching similar values as biparentally raised animals in adulthood. However, in adulthood reduced apical spine numbers together with shorter apical dendrites were observed in father-deprived animals, which indicates that dendritic growth and synapse formation (seen in biparental animals between postnatal day 21 and adulthood) were significantly suppressed. These results demonstrate that paternal deprivation delays and partly suppresses the development of orbitofrontal circuits. The retarded dendritic and synaptic development of the apical dendrites of layer II/III pyramidal neurons in the orbitofrontal cortex of adult fatherless animals may reflect a reduced excitatory connectivity of this cortical subregion.

  13. Developmental Origin of Patchy Axonal Connectivity in the Neocortex: A Computational Model

    PubMed Central

    Bauer, Roman; Zubler, Frederic; Hauri, Andreas; Muir, Dylan R.; Douglas, Rodney J.

    2014-01-01

    Injections of neural tracers into many mammalian neocortical areas reveal a common patchy motif of clustered axonal projections. We studied in simulation a mathematical model for neuronal development in order to investigate how this patchy connectivity could arise in layer II/III of the neocortex. In our model, individual neurons of this layer expressed the activator–inhibitor components of a Gierer–Meinhardt reaction–diffusion system. The resultant steady-state reaction–diffusion pattern across the neuronal population was approximately hexagonal. Growth cones at the tips of extending axons used the various morphogens secreted by intrapatch neurons as guidance cues to direct their growth and invoke axonal arborization, so yielding a patchy distribution of arborization across the entire layer II/III. We found that adjustment of a single parameter yields the intriguing linear relationship between average patch diameter and interpatch spacing that has been observed experimentally over many cortical areas and species. We conclude that a simple Gierer–Meinhardt system expressed by the neurons of the developing neocortex is sufficient to explain the patterns of clustered connectivity observed experimentally. PMID:23131803

  14. Effects of Mood Stabilizers on Brain Energy Metabolism in Mice Submitted to an Animal Model of Mania Induced by Paradoxical Sleep Deprivation.

    PubMed

    Streck, Emilio L; Scaini, Giselli; Jeremias, Gabriela C; Rezin, Gislaine T; Gonçalves, Cinara L; Ferreira, Gabriela K; Réus, Gislaine Z; Resende, Wilson R; Valvassori, Samira S; Kapczinski, Flávio; Andersen, Mônica L; Quevedo, João

    2015-06-01

    There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II-III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II-III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

  15. Accident progression event tree analysis for postulated severe accidents at N Reactor

    SciTech Connect

    Wyss, G.D.; Camp, A.L.; Miller, L.A.; Dingman, S.E.; Kunsman, D.M. ); Medford, G.T. )

    1990-06-01

    A Level II/III probabilistic risk assessment (PRA) has been performed for N Reactor, a Department of Energy (DOE) production reactor located on the Hanford reservation in Washington. The accident progression analysis documented in this report determines how core damage accidents identified in the Level I PRA progress from fuel damage to confinement response and potential releases the environment. The objectives of the study are to generate accident progression data for the Level II/III PRA source term model and to identify changes that could improve plant response under accident conditions. The scope of the analysis is comprehensive, excluding only sabotage and operator errors of commission. State-of-the-art methodology is employed based largely on the methods developed by Sandia for the US Nuclear Regulatory Commission in support of the NUREG-1150 study. The accident progression model allows complex interactions and dependencies between systems to be explicitly considered. Latin Hypecube sampling was used to assess the phenomenological and systemic uncertainties associated with the primary and confinement system responses to the core damage accident. The results of the analysis show that the N Reactor confinement concept provides significant radiological protection for most of the accident progression pathways studied.

  16. Receptive field scatter, topography and map variability in different layers of the hindpaw representation of rat somatosensory cortex.

    PubMed

    Haupt, S Shuichi; Spengler, Friederike; Husemann, Robert; Dinse, Hubert R

    2004-04-01

    We recorded neurons extracellularly in layers II/III, IV, and V of the hindpaw representation of primary somatosensory cortex in anesthetized rats and studied laminar features of receptive fields (RFs) and representational maps. On average, RFs were smallest in layer IV and largest in layer V; however, for individual penetrations we found substantial deviations from this rule. Within the hindpaw representation, a distinct rostrocaudal gradient of RF size was present in all layers. While layer V RFs were generally largest independent of this gradient, layer IV RFs recorded caudally representing the proximal portions of the paw were larger than layer II/III RFs recorded rostrally representing the digits. The individual scatter of the locations of RFs across laminar groups was in the range of several millimeters, corresponding to about 25% of the average RF diameter. The cutaneous representations of the hindpaw in extragranular layers were confined to the areal extent defined by responsive sites in layer IV. Comparison between RFs determined quantitatively and by handplotting showed a reliable correspondence. Repeated measurements of RFs revealed spontaneous fluctuations of RF size of no more than 5% of the initial condition over an observation period of several hours. The topography and variability of cortical maps of the hindpaw representation were studied with a quantitative interpolation method taking into account the geometric centers of RFs and the corresponding cortical recording sites. On average, the overall topography in terms of preservation of neighborhood relations was present in all layers, although some individual maps showed severe distortions of topography. Factors contributing to map variability were overall position of the representation on the cortical surface, internal topography and spatial extent. Interindividual variability of map layout was always highest in the digit representations. Local topographic orderliness was lowest in layer V, but

  17. Animal models of rheumatoid arthritis: How informative are they?

    PubMed

    McNamee, Kay; Williams, Richard; Seed, Michael

    2015-07-15

    Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.

  18. Development of InCVAX as a novel in situ autologous vaccine for metastatic cancers (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel Siu Kit; Nordquist, Robert E.; Chen, Wei R.

    2016-03-01

    A novel method, an in situ autologous whole-cell cancer vaccine (inCVAX), is being developed by Immunophotonics, Inc., for the treatment of metastatic cancers. inCVAX combines phototherapy and immunotherapy to potentially induce a systemic anti-tumor immune response in the hosts. Immunophotonics and its academic partners have spent years conducting nonclinical research, developing CMC techniques and conducting clinical research. In 2015 the company initiated a late-stage (II/III) clinical trial in South America for advanced breast cancer patients. The process of developing the inCVAX approach from a laboratory setting into clinical trials requires significant efforts from a group of dedicated engineers, scientists, and physicians. The growth of the company and its business advances demonstrated the determination of a group of visionary investors, entrepreneurs, and business leaders. This talk will chronicle the milestones of the scientific achievement, medical progress, and business development of Immunophotonics.

  19. Ceftazidime-avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections.

    PubMed

    Mawal, Yogesh; Critchley, Ian A; Riccobene, Todd A; Talley, Angela K

    2015-01-01

    Treatment of complicated urinary tract infections and complicated intra-abdominal infections is increasingly difficult due to the rising prevalence of multidrug-resistant Gram-negative bacteria. Ceftazidime-avibactam is a combination of the established third-generation cephalosporin ceftazidime with avibactam, a novel non-β-lactam β-lactamase inhibitor, which restores the activity of ceftazidime against many β-lactamase-producing Gram-negative bacteria, including extended-spectrum β-lactamases and Klebsiella pneumoniae carbapenemases. Clinical and nonclinical studies supporting the safety and efficacy of ceftazidime-avibactam include microbiological surveillance studies of clinically relevant pathogens, in vivo animal models of infection, pharmacokinetic/pharmacodynamic target attainment analyses, Phase I clinical pharmacology studies, and Phase II/III studies in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including patients with ceftazidime-nonsusceptible Gram-negative infections.

  20. Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells

    PubMed Central

    Walker, F.; Möck, M.; Feyerabend, M.; Guy, J.; Wagener, R. J.; Schubert, D.; Staiger, J. F.; Witte, M.

    2016-01-01

    Disinhibition of cortical excitatory cell gate information flow through and between cortical columns. The major contribution of Martinotti cells (MC) is providing dendritic inhibition to excitatory neurons and therefore they are a main component of disinhibitory connections. Here we show by means of optogenetics that MC in layers II/III of the mouse primary somatosensory cortex are inhibited by both parvalbumin (PV)- and vasoactive intestinal polypeptide (VIP)-expressing cells. Paired recordings revealed stronger synaptic input onto MC from PV cells than from VIP cells. Moreover, PV cell input showed frequency-independent depression, whereas VIP cell input facilitated at high frequencies. These differences in the properties of the two unitary connections enable disinhibition with distinct temporal features. PMID:27897179

  1. National Dam Safety Program. Van Meter Dam (MO 10658), Missouri - Kansas City Basin, Saline County, Missouri. Phase I Inspection Report.

    DTIC Science & Technology

    1978-12-01

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  2. Abnormal Auditory Brainstem Response (ABR) Findings in a Near-Normal Hearing Child with Noonan Syndrome

    PubMed Central

    Jalaei, Bahram; Zakaria, Mohd Normani; Sidek, Dinsuhaimi

    2017-01-01

    Introduction: Noonan syndrome (NS) is a heterogeneous genetic disease that affects many parts of the body. It was named after Dr. Jacqueline Anne Noonan, a paediatric cardiologist. Case Report: We report audiological tests and auditory brainstem response (ABR) findings in a 5-year old Malay boy with NS. Despite showing the marked signs of NS, the child could only produce a few meaningful words. Audiological tests found him to have bilateral mild conductive hearing loss at low frequencies. In ABR testing, despite having good waveform morphology, the results were atypical. Absolute latency of wave V was normal but interpeak latencies of wave’s I-V, I-II, II-III were prolonged. Interestingly, interpeak latency of waves III-V was abnormally shorter. Conclusion: Abnormal ABR results are possibly due to abnormal anatomical condition of brainstem and might contribute to speech delay. PMID:28229064

  3. [Child abuse in Tlaxcala: a case-control study].

    PubMed

    Herrada-Huidobro, A; Nazar-Beutelspacher, A; Cassaball-Núñez, M; Vega-Ramos, R; Nava-Cruz, C B

    1992-01-01

    A longitudinal, retrospective and descriptive study about child abuse was carried out in the Hospitals of the Tlaxcala Secretariat of Health, Mexico. The information was obtained from hospitalized children's charts between January first and November 30, 1991. The charts included were those belonging to zero to 14 year old children with injuries, poisoning, and II-III degrees of malnutrition. Four child-abuse criteria were established: physical, sexual, non organic malnutrition and mixed (physical and non organic malnutrition). Two control groups were defined. Different patterns were observed between accidental and non accidental injuries, malnutrition and poisoning among the case and the control groups. The study provides useful information for the integral diagnosis of child abuse in hospitalized children.

  4. Statistical inference for response adaptive randomization procedures with adjusted optimal allocation proportions.

    PubMed

    Zhu, Hongjian

    2016-12-12

    Seamless phase II/III clinical trials have attracted increasing attention recently. They mainly use Bayesian response adaptive randomization (RAR) designs. There has been little research into seamless clinical trials using frequentist RAR designs because of the difficulty in performing valid statistical inference following this procedure. The well-designed frequentist RAR designs can target theoretically optimal allocation proportions, and they have explicit asymptotic results. In this paper, we study the asymptotic properties of frequentist RAR designs with adjusted target allocation proportions, and investigate statistical inference for this procedure. The properties of the proposed design provide an important theoretical foundation for advanced seamless clinical trials. Our numerical studies demonstrate that the design is ethical and efficient.

  5. The use of capecitabine in the combined-modality therapy for rectal cancer.

    PubMed

    Liauw, Stanley L; Minsky, Bruce D

    2008-03-01

    Locally advanced rectal adenocarcinoma is treated by combined-modality therapy, which consists of surgery, chemotherapy, and radiation therapy. A series of randomized trials established a preferred treatment sequence of preoperative radiation therapy and 5-fluorouracil(5-FU)-based chemotherapy, total mesorectal excision, and adjuvant 5-FU-based chemotherapy for patients with stage II/III disease. Capecitabine is an oral prodrug of 5-FU that has potential advantages compared with intravenous 5-FU, including ease of administration and potentially increased therapeutic effect. Capecitabine is converted by a 3-step enzymatic process; the last step involves the enzyme thymidine phosphorylase, which is overexpressed in tumor tissues and is stimulated by concurrent radiation therapy. Over the past 5 years, several phase I/II trials of capecitabine-based therapy were reported. This review discusses the evolution of combined-modality therapy for rectal cancer with specific attention given to the use of capecitabine in conjunction with radiation therapy.

  6. Listing of Army Fuel-Consuming Nonautomotive Ground Support Equipment.

    DTIC Science & Technology

    1981-08-01

    W Z(55I(00W(.J...J0((55(5 X55(S NNN. .6uu m xv~ 00d0. . -z 00 0 0a0 e~ W 0 0 1fl 0 40.28 QUf0=Q lS59uuIIIII 4 a a acca N0QgI %q c a It, 4t 0 0 0 - !3...QO c~lCS- VIC X00 woo" )- 00 0*U- OKKKK3S33S300 xwC w A IWZ -I 2 In -m0N~ - P1 - --- - 004M43101 S C t4IMY-40 £I39M 93 ~ ~ KK A .- I, I - - .- I. 0 0

  7. Proposal for a "phase II" multicenter trial model for preclinical new antiepilepsy therapy development.

    PubMed

    O'Brien, Terence J; Ben-Menachem, Elinor; Bertram, Edward H; Collins, Stephen D; Kokaia, Merab; Lerche, Holger; Klitgaard, Henrik; Staley, Kevin J; Vaudano, Elisabetta; Walker, Matthew C; Simonato, Michele

    2013-08-01

    There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.

  8. Efficient Ab initio Modeling of Random Multicomponent Alloys.

    PubMed

    Jiang, Chao; Uberuaga, Blas P

    2016-03-11

    We present in this Letter a novel small set of ordered structures (SSOS) method that allows extremely efficient ab initio modeling of random multicomponent alloys. Using inverse II-III spinel oxides and equiatomic quinary bcc (so-called high entropy) alloys as examples, we demonstrate that a SSOS can achieve the same accuracy as a large supercell or a well-converged cluster expansion, but with significantly reduced computational cost. In particular, because of this efficiency, a large number of quinary alloy compositions can be quickly screened, leading to the identification of several new possible high-entropy alloy chemistries. The SSOS method developed here can be broadly useful for the rapid computational design of multicomponent materials, especially those with a large number of alloying elements, a challenging problem for other approaches.

  9. AGARD Flight Test Techniques Series. Volume 5. Store Separation Flight Testing

    DTIC Science & Technology

    1986-04-01

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  10. The influence of the call with a mobile phone on heart rate variability parameters in healthy volunteers.

    PubMed

    Andrzejak, Ryszard; Poreba, Rafal; Poreba, Malgorzata; Derkacz, Arkadiusz; Skalik, Robert; Gac, Pawel; Beck, Boguslaw; Steinmetz-Beck, Aleksandra; Pilecki, Witold

    2008-08-01

    It is possible that electromagnetic field (EMF) generated by mobile phones (MP) may have an influence on the autonomic nervous system (ANS) and modulates the function of circulatory system. The aim of the study was to estimate the influence of the call with a mobile phone on heart rate variability (HRV) in young healthy people. The time and frequency domain HRV analyses were performed to assess the changes in sympathovagal balance in a group of 32 healthy students with normal electrocardiogram (ECG) and echocardiogram at rest. The frequency domain variables were computed: ultra low frequency (ULF) power, very low frequency (VLF) power, low frequency (LF) power, high frequency (HF) power and LF/HF ratio was determined. ECG Holter monitoring was recorded in standardized conditions: from 08:00 to 09:00 in the morning in a sitting position, within 20 min periods: before the telephone call (period I), during the call with use of mobile phone (period II), and after the telephone call (period III). During 20 min call with a mobile phone time domain parameters such as standard deviation of all normal sinus RR intervals (SDNN [ms]--period I: 73.94+/-25.02, period II: 91.63+/-35.99, period III: 75.06+/-27.62; I-II: p<0.05, II-III: p<0.05) and standard deviation of the averaged normal sinus RR intervals for all 5-mm segments (SDANN [ms]--period I: 47.78+/-22.69, period II: 60.72+/-27.55, period III: 47.12+/-23.21; I-II: p<0.05, II-III: p<0.05) were significantly increased. As well as very low frequency (VLF [ms2]--period I: 456.62+/-214.13, period II: 566.84+/-216.99, period III: 477.43+/-203.94; I-II: p<0.05), low frequency (LF [ms(2)]--period I: 607.97+/-201.33, period II: 758.28+/-307.90, period III: 627.09+/-220.33; I-II: p<0.01, II-III: p<0.05) and high frequency (HF [ms(2)]--period I: 538.44+/-290.63, period II: 730.31+/-445.78, period III: 590.94+/-301.64; I-II: p<0.05) components were the highest and the LF/HF ratio (period I: 1.48+/-0.38, period II: 1

  11. Prevalence and genotype identification of Toxoplasma gondii in wild animals from southwestern Spain.

    PubMed

    Calero-Bernal, Rafael; Saugar, José M; Frontera, Eva; Pérez-Martín, Juan E; Habela, Miguel A; Serrano, Francisco J; Reina, David; Fuentes, Isabel

    2015-01-01

    We used PCR to detect Toxoplasma gondii in the principal game species in southwestern Spain. We detected T. gondii in 32.2% of animals tested. Prevalences varied from 14.7% in wild boar (Sus scrofa) to 51.2% in red fox (Vulpes vulpes). The most prevalent genotype was type II (50.0%), followed by type III (20.6%) and type I (5.9%). Mixed infections (11.8%) were detected in wild boar (types I+III) and red fox (types II+III). Polymorphic strains (11.8%) were detected in several species. The high prevalence and the genetic variability shown could have implications for infection of farm animals and humans.

  12. Differential Gene Expression Reveals Mitochondrial Dysfunction in an Imprinting Center Deletion Mouse Model of Prader-Willi Syndrome

    PubMed Central

    Fan, Weiwei; Coskun, Pinar E.; Nalbandian, Angèle; Knoblach, Susan; Resnick, James L.; Hoffman, Eric; Wallace, Douglas C.; Kimonis, Virginia E.

    2013-01-01

    Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity and diabetes. Previous clinical studies suggest that a defect in energy metabolism may be involved in the pathogenesis of PWS. We focused our attention on the genes associated with energy metabolism and found that there were 95 and 66 mitochondrial genes differentially expressed in PWS muscle and brain, respectively. Assessment of enzyme activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes in the brain, heart, liver and muscle were assessed. We found the enzyme activities of the cardiac mitochondrial complexes II+III were upregulated in the imprinting center deletion (PWS-IC) mice compared to the wild type littermates. These studies suggest that differential gene expression, especially of the mitochondrial genes may contribute to the pathophysiology of PWS. PMID:24127921

  13. [Bacteria ecology in planting-culturing system].

    PubMed

    Huang, Fenglian; Xia, Beicheng; Dai, Xin; Chen, Guizhu

    2004-06-01

    Planting-culturing system in inter-tidal zone is a new type eco-culturing model. The survey on bacteria biomass and water quality in the designed planting-culturing system in inter-tidal zone showed that the mangrove planted in the system improved water quality and made water quality to II-III type, better than the IV and V type in the control pond. Designed ponds made heterotrophic bacteria, vibrio, phosphorus bacteria and enzyme-producing bacteria populations 1-2 order lower than the control pond without mongrove planting. Correlation analyses with CORREL software showed that the biomass of these bacteria was positively related with the nitrogen and phosphorus contents in water of the system, and the correlation coefficient for heterogeneous bacteria and vibrio was up to 0.9205. Heterotrophic bacteria and vibrio could be used as the water-quality monitoring organisms.

  14. Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A.

    PubMed

    Gomperts, Edward

    2015-08-01

    Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r-pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA.

  15. Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis.

    PubMed

    Comim, Clarissa M; Freiberger, Viviane; Ventura, Letícia; Mina, Francielle; Ferreira, Gabriela K; Michels, Monique; Generoso, Jaqueline S; Streck, Emílio L; Quevedo, João; Barichello, Tatiana; Dal-Pizzol, Felipe

    2017-04-15

    Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that may affect the brain. We investigated the role of indoleamine 2,3-dioxygenase (IDO-1/2) inhibition on long-term memory and energetic metabolism after experimental sepsis by caecal ligation and perforation (CLP). Experimental sepsis increased the activity of complexes I, II-III and IV at 24h after CLP, and IDO-1/2 inhibition normalized the activity of these complexes in the hippocampus. Wistar rats presented impairment of habituation and aversive memories 10days after CLP. Adjuvant treatment with the IDO inhibitor prevented long-term cognitive impairment triggered by sepsis.

  16. VizieR Online Data Catalog: Oxygen recombination lines from Cas A knots (Docenko+, 2008)

    NASA Astrophysics Data System (ADS)

    Docenko, D.; Sunyaev, R. A.

    2008-03-01

    Tables contain wavelengths and intensities or emissivities of the fine structure components of the O, Si and S ion optical and near-infrared recombination lines (RLs) in the (nlK) -> (n'l'K') resolution. Emissivities and wavelengths are given for O II-VI, Si II-III and S II-V ion {alpha}-, {beta}- and {gamma}-line components in the wavelength range between 0.3 and 5 micron and temperature range between 103 and 105K. Only low-density emissivity values are included in tables and only transitions onto levels with nl>=5 are considered. Intensities and wavelengths are given for O II-VI ion {alpha}-, {beta}- and {gamma}-line components in the same wavelength range, as computed based on the Sutherland & Dopita (1995ApJ...439..381S) model of the oxygen-rich plasma emission in supernova remnants applied to Cassiopeia A fast-moving knots. (19 data files).

  17. Fermentation, Hydrogen, and Sulfur Metabolism in Multiple Uncultivated Bacterial Phyla

    SciTech Connect

    Wrighton, Kelly C.; Thomas, BC; Sharon, I; Miller, CS; Castelle, Cindy J; Verberkmoes, Nathan C; Wilkins, Michael J.; Hettich, Robert {Bob} L; Lipton, Mary S; Williams, Ken; Long, Philip E; Banfield, Jillian F.

    2012-01-01

    BD1-5, OP11, and OD1 bacteria have been widely detected in anaerobic environments, but their metabolisms remain unclear owing to lack of cultivated representatives and minimal genomic sampling. We uncovered metabolic characteristics for members of these phyla, and a new lineage, PER, via cultivation-independent recovery of 49 partial to near-complete genomes from an acetate-amended aquifer. All organisms were nonrespiring anaerobes predicted to ferment. Three augment fermentation with archaeal-like hybrid type II/III ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO) that couples adenosine monophosphate salvage with CO2 fixation, a pathway not previously described in Bacteria. Members of OD1 reduce sulfur and may pump protons using archaeal-type hydrogenases. For six organisms, the UGA stop codon is translated as tryptophan. All bacteria studied here may play previously unrecognized roles in hydrogen production, sulfur cycling, and fermentation of refractory sedimentary carbon.

  18. New species and records of Microveliinae and Veliinae (Hemiptera: Heteroptera: Veliidae) from Colombia.

    PubMed

    Molano, Fredy; Moreira, Felipe Ferraz Figueiredo; Morales, Irina

    2016-09-29

    Euvelia orinoquia sp. nov. and E. meta sp. nov. from eastern Colombia are described, illustrated, and included in an updated identification key to the species of the genus. The former can be diagnosed by body length 2.30-2.50 mm, male fore femur without tufts of setae, longitudinal black stripe of female pronotum almost twice as wide as length of antennomere I, and female connexiva grayish black with silvery pruinosity on mesal portion, reddish on lateral portion. Euvelia meta sp. nov. can be diagnosed by female body length about 1.50 mm and maximum body width 0.90 mm, patches of silvery setae on female abdominal terga II-III and V-VII, and connexival segments I and IV-VI. Additionally, new records from the country are presented for species of Euvelia Drake, Husseyella Herring, Microvelia Westwood (Microveliinae), Oiovelia Drake & Maldonado-Capriles, Platyvelia Polhemus & Polhemus, Stridulivelia Hungerford, and Veloidea Gould (Veliinae).

  19. Re-entrant spin glass and stepped magnetization in mixed-valence SrFe3(PO4)3

    NASA Astrophysics Data System (ADS)

    Shang, Mingyu; Chen, Yan; Tian, Ge; Yuan, Hongming; Feng, Shouhua

    2013-01-01

    The 2 D channel mixed-valent iron (II/III) monophosphate SrFe3(PO4)3 was synthesized via one step mild hydrothermal method at 210 °C and characterized by X-ray diffraction techniques and magnetization measurements. Coexistence of antiferromagnetic superexchange and ferromagnetic superexchange interactions was supposed to be in the lattice according to the Goodenough-Kanamori-Anderson rules. Temperature dependent DC magnetization measurement shows that SrFe3(PO4)3 is ferrimagnet with three magnetic transitions between 2 and 350 K. Through AC magnetization measurement, re-entrant spin glass was observed due to the competition between ferromagnetic and antiferromagnetic interactions. Furthermore, an interesting field induced stepped magnetization was observed in SrFe3(PO4)3 at 2 K with the saturation magnetization Ms=2.4 μB/f.u. at 5 T.

  20. Atopic eczema.

    PubMed

    Brown, Sara J

    2016-02-01

    Atopic eczema is an itchy inflammatory skin disease with a chronic relapsing-remitting course; it has increased in prevalence in recent decades and now affects up to 25% of school-aged children in the developed world and up to 10% of adults. Recent advances in understanding the aetiology of eczema have focused interest on skin barrier dysfunction as a common precursor and pathological feature. In addition, genetically determined skin barrier dysfunction (associated with mutations in the gene encoding filaggrin) is known to predispose to multiple systemic atopic diseases. First-line treatments for atopic eczema focus on maintaining and repairing the skin barrier (emollients) and reducing inflammation (topical steroids); allergen and irritant avoidance are also important to achieve disease control. Second and third-line treatments include topical calcineurin inhibitors, ultraviolet light and systemic immunosuppressant therapies of which only ciclosporin is licenced for the treatment of atopic eczema in adults. Novel biological therapies are in phase II-III clinical trials.

  1. Clinical pharmacology considerations in biologics development

    PubMed Central

    Zhao, Liang; Ren, Tian-hua; Wang, Diane D

    2012-01-01

    Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram. PMID:23001474

  2. Progression of Ebola Therapeutics During the 2014-2015 Outbreak.

    PubMed

    Mendoza, Emelissa J; Qiu, Xiangguo; Kobinger, Gary P

    2016-02-01

    The recent Ebola virus (EBOV) outbreak in West Africa was the deadliest EBOV epidemic in history, highlighting the need for a safe and efficacious treatment against EBOV disease (EVD). In the absence of an approved treatment, experimental drugs were utilized under compassionate grounds hoping to diminish EVD-associated morbidity and mortality. As more data were collected from safety studies, Phase II/III clinical trials were introduced in Guinea, Sierra Leone, and Liberia to test promising candidates, including small-molecule drugs, RNA-based treatments, and antibody-based therapies. In this review, we summarize the use of, and preliminary observations from, current clinical trials with EVD therapeutics, shedding light on experimental drug selection, emergency clinical evaluation, and the impact these factors may have on future infectious disease outbreaks.

  3. Energy approach to the problem of calculating the stresses at the initial stages of plastic deformation of crystalline substances and the appearance of structural defects

    NASA Astrophysics Data System (ADS)

    Belousov, O. K.; Palii, N. A.

    2016-09-01

    The critical shear stress and its temperature dependence are calculated for 12 simple substances with different structures and types of bonding. The shear stress for stage II-III of deformation of single crystals (τII-III) and σ0, y, i.e., the Hall-Petch relation extrapolated to an infinitely large grain size, are estimated. The energy of formation of lattice defects (vacancies) is calculated using a proposed expression. The results of calculation of the elastic shear energy of a matrix and regions with a high elastic anisotropy are used to estimate the role of elastic anisotropy in lattice stability and fracture. The calculated and experimental results agree satisfactorily with each other.

  4. Cholinergic and noradrenergic triggers' in soman induced convulsions

    SciTech Connect

    Shipley, M.T.; Zimmer, L.; Ennis, M.; Etri, M.

    1993-05-13

    Considerable evidence suggests that soman induced seizure's are initiated in the piriform cortex (PC). Consistent with this, PC is the most frequent site of neuropathology in soman treated rats and other species. Previous studies in this laboratory have shown that convulsive doses of soman cause the rapid induction of the immediate early gene protein product, Fos, in piriform cortex (PC). Fos is known to be expressed when neurons undergo sustained excitatory activity. Following soman, Fos is selectively expressed by neurons in layers II Ill of PC. These neurons are known to send excitatory projections to the hippocampus and to thalamus and neocortex. Thus, we have suggested that soman may initially cause seizure activity in layer II-III PC neurons; this seizure activity could then spread to the hippocampus and neocortex. Consistent with this hypothesis, we have observed that Fos is expressed in hippocampus, thalamus and neocortex subsequent to its expression in PC.

  5. Main determinants of physical activity levels in individuals with Parkinson's disease.

    PubMed

    Lana, Raquel de Carvalho; de Araujo, Lysandra Nogueira; Cardoso, Francisco; Rodrigues-de-Paula, Fátima

    2016-02-01

    This study analyzed the relationship between patient characteristics, factors associated with Parkinson's disease (PD), and physical activity level of individuals affected by the disease. Forty-six volunteers with mild-to-moderate idiopathic PD were assessed using sections II/III of the Unified Parkinson's Disease Rating Scale and their motor functions were classified according to the modified Hoehn and Yahr (HY) scale. Data such as age, disease duration, the Human Activity Profile (HAP), the Fatigue Severity Scale were collected. Lower limb bradykinesia and clinical subtypes of PD were defined. Two models that explained 76% of the variance of the HAP were used. The first comprised age, ability to perform activities of daily living (ADL), and the HY scale; the second comprised age, ability to perform ADL, and lower limb bradykinesia. Possible modifiable factors such as the ability to perform ADL and lower limb bradykinesia were identified as predictors of physical activity level of individuals with PD.

  6. Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer

    PubMed Central

    McFarland, Daniel C; Misiukiewicz, Krzysztof J

    2014-01-01

    Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials. PMID:25053887

  7. Imaging of the stroke-related changes in the vascular system of the mouse brain with the use of extended focus optical coherence microscopy

    NASA Astrophysics Data System (ADS)

    Tamborski, Szymon; Lyu, Hong Chou; Bukowska, Danuta; Dolezyczek, Hubert; Wilczynski, Grzegorz; Szlag, Daniel; Lasser, Theo; Wojtkowski, Maciej; Szkulmowski, Maciej

    2016-03-01

    We used Optical Coherence Microscopy (OCM) to monitor structural and functional changes due to ischemic stroke in small animals brains in vivo. To obtain lateral resolution of 2.2 μm over the range of 600 μm we used extended focus configuration of OCM instrument involving Bessel beam. It provided access to detailed 3D information about the changes in brain vascular system up to the level of capillaries across I and II/III layers of neocortex. We used photothrombotic stroke model involving photoactive application of rose bengal to assure minimal invasiveness of the procedure and precise localization of the clot distribution center. We present the comparative analysis involving structural and angiographic maps of the stroke-affected brain enabling in-depth insight to the process of development of the disorder.

  8. [Morphogenesis of connective tissue in patients with hydronephrosis caused by stricture of ureteric-pelvic segment of various etiology].

    PubMed

    Savenkov, V I

    2015-02-01

    In patients, suffering hydronephrosis stages II-III, caused by the ureteric-pelvic segment (UPS) obstruction due to inborn failures of urinary system, the collagen types I and III ratio reduction, and in acquired obstruction--its enhancement, are noted in interstitium, renal parenchyma vessels and the UPS walls. While obstruction in patients due to inborn failures in vascular basal membranes a deficiency of collagen type IV and appearance of nontypical for vascular basal membranes intersticial collagen type Il are observed. In the acquired UPS, obstruction the, enhancement of content of collagen type IV is revealed only. These disorders are mostly pronounced in patients with the disease recurrence. There was proposed diagnostic coefficient of ratio between collagens types I and III in patients, suffering hydronephrosis, caused by obstruction of various etiology. In hydronephrosis, caused by the UPS stricture, the cytokines disbalance occurs, impacting processes of collagen formation.

  9. Decoding the stellar fossils of the dusty Milky Way progenitors

    NASA Astrophysics Data System (ADS)

    de Bennassuti, M.; Schneider, R.; Valiante, R.; Salvadori, S.

    2014-12-01

    We investigate the metallicity distribution function (MDF) of the Galactic halo and the relative fraction of Carbon-normal and Carbon-rich stars using the semi-analytical code GAMETE. The code reconstructs the hierarchical merger tree of the Milky Way (MW) and follows the star formation history and the metal evolution in individual progenitors, including for the first time the formation and evolution of dust. We predict scaling relations between the dust, metal and gas masses for MW progenitors and compare them with observational data of galaxies at 0 <= z < 6.3. We find that the relative contribution of C-normal and C-enhanced stars to the MDF and its dependence on [Fe/H] allow to discriminate among different Pop III/II transition criteria as well as between different Initial Mass Functions (IMFs) and supernova (SN) yields for Population III stars.

  10. Reliability Parts Derating Guidelines

    DTIC Science & Technology

    1982-06-01

    COMM1ANDEZR4% JORI1 P. RUSIS" Ac~ttng ChiiK!i Plans COEiee If your address has changed or if you wtiah to bek reuov$d f ret theRAC mailing list, or If...equipment: Space, Flight; Missile, Launch; Military 25 I ......- ,-,- MII-STD-1547: Parts, Materials and Processes for Space and Launch Vehicles, Technical...3 1.4 UN1 5 25 12 21 2•544 1 49 25 11 31 F .5 I5 . ,Ui 2- Iiiii TIN&M FW VI i T I BWIRWEIMT MMI 0 W• 1 AIT AIT AIF F B 1. ML W WS 1t .3 .1 1 .75 .75

  11. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation.

    PubMed

    Corbacioglu, Selim; Kernan, Nancy; Lehmann, Leslie; Brochstein, Joel; Revta, Carolyn; Grupp, Stephan; Martin, Paul; Richardson, Paul G

    2012-06-01

    Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.

  12. CHEMINI: A new in situ CHEmical MINIaturized analyzer

    NASA Astrophysics Data System (ADS)

    Vuillemin, R.; Le Roux, D.; Dorval, P.; Bucas, K.; Sudreau, J. P.; Hamon, M.; Le Gall, C.; Sarradin, P. M.

    2009-08-01

    "CHEMINI" is a new instrument developed for the measurement of seawater chemical parameters. It is a mono-parameter in situ chemical analyzer based on flow injection analysis and colorimetric detection. The deep-sea version of CHEMINI combines two modules to perform the analysis of dissolved iron [Fe (II) or Fe (II+III)] and total sulphide (H 2S+HS -+S 2-) up to 6000 m depth. Detection limits are, respectively, 0.3 and 0.1 μM for iron and sulphide. The system proved highly reliable during the MoMARETO cruise on the Mid-Atlantic Ridge. The two CHEMINIs were used to describe the chemical environment in 12 mussel beds on the Tour Eiffel hydrothermal edifice.

  13. Percutaneous mitral valve repair with MitraClip for severe functional mitral regurgitation.

    PubMed

    Yeo, Khung Keong; Ding, Zee Pin; Chua, Yeow Leng; Lim, Soo Teik; Sin, Kenny Yoong Kong; Tan, Jack Wei Chieh; Chiam, Paul Toon Lim; Hwang, Nian Chih; Koh, Tian Hai

    2013-01-01

    A 67-year-old Chinese woman with comorbidities of chronic obstructive lung disease, hypertension and prior coronary artery bypass surgery presented with severe functional mitral regurgitation (MR) and severely depressed left ventricular function. She was in New York Heart Association (NYHA) Class II-III. Due to high surgical risk, she was referred for percutaneous treatment with the MitraClip valve repair system. This procedure is typically performed via the femoral venous system and involves a transseptal puncture. A clip is delivered to grasp the regurgitant mitral valve leaflets and reduce MR. This was performed uneventfully in our patient, with reduction of MR from 4+ to 1+. She was discharged on post-procedure Day 2 and her NYHA class improved to Class I. This was the first successful MitraClip procedure performed in Asia and represents a valuable treatment option in patients with severe MR, especially those with functional MR or those at high surgical risk.

  14. Ofatumumab for a rituximab-allergic child with chronic-relapsing paraneoplastic opsoclonus-myoclonus.

    PubMed

    Pranzatelli, Michael R; Tate, Elizabeth D; Shenoy, Shalini; Travelstead, Anna L

    2012-06-01

    Ofatumumab is a fully human anti-CD20 monoclonal antibody in phase II-III trials for various autoimmune and lymphoreticular diseases. We used it to treat a rituximab-allergic child with severe, chronic-relapsing, opsoclonus-myoclonus syndrome (OMS), characterized by persistent cerebrospinal fluid (CSF) B-cell expansion and T-cell dysregulation. He had relapsed despite chemotherapy, plasma exchange with immunoadsorption, and resection of ganglioneuroblastoma, detected 3 years after OMS onset. The four ofatumumab infusions (1,195 mg/m(2) total dose) were well tolerated, and CSF B-cell expansion was eliminated. No further relapses have occurred in 3 years, but he remains on low-dose ACTH with neuropsychiatric residuals of OMS.

  15. Molecular Markers in Low-Grade Glioma-Toward Tumor Reclassification.

    PubMed

    Olar, Adriana; Sulman, Erik P

    2015-07-01

    Low-grade diffuse gliomas are a heterogeneous group of primary glial brain tumors with highly variable survival. Currently, patients with low-grade diffuse gliomas are stratified into risk subgroups by subjective histopathologic criteria with significant interobserver variability. Several key molecular signatures have emerged as diagnostic, prognostic, and predictor biomarkers for tumor classification and patient risk stratification. In this review, we discuss the effect of the most critical molecular alterations described in diffuse (IDH1/2, 1p/19q codeletion, ATRX, TERT, CIC, and FUBP1) and circumscribed (BRAF-KIAA1549, BRAF(V600E), and C11orf95-RELA fusion) gliomas. These molecular features reflect tumor heterogeneity and have specific associations with patient outcome that determine appropriate patient management. This has led to an important, fundamental shift toward developing a molecular classification of World Health Organization grade II-III diffuse glioma.

  16. The potential for a controlled human infection platform in Singapore

    PubMed Central

    Balasingam, Shobana; Horby, Peter; Wilder-Smith, Annelies

    2014-01-01

    For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies. PMID:25273928

  17. Enhanced Vision for All-Weather Operations Under NextGen

    NASA Technical Reports Server (NTRS)

    Bailey, Randall E.; Kramer, Lynda J.; Williams, Steven P.; Bailey, Randall E.; Kramer, Lynda J.; Williams, Steven P.

    2010-01-01

    Recent research in Synthetic/Enhanced Vision technology is analyzed with respect to existing Category II/III performance and certification guidance. The goal is to start the development of performance-based vision systems technology requirements to support future all-weather operations and the NextGen goal of Equivalent Visual Operations. This work shows that existing criteria to operate in Category III weather and visibility are not directly applicable since, unlike today, the primary reference for maneuvering the airplane is based on what the pilot sees visually through the "vision system." New criteria are consequently needed. Several possible criteria are discussed, but more importantly, the factors associated with landing system performance using automatic and manual landings are delineated.

  18. The n-CdSe photoelectrochemical cell: wavelength-dependent photostability

    SciTech Connect

    Rubin, H.D.; Arent, D.J.; Bocarsly, A.B.

    1985-02-01

    Much recent work has focused on Fe(CN)/sub 6/ /SUP 4-/3-/ as a stabilizing electrolyte for n-CdX(X=S,Se) based photoelectrochemical cells (1-5). Prior studies performed in this laboratory (6) showed that irradiation of n-CdS in an electrolyte containing Fe(CN)/sub 6/ /SUP 4-/3-/ can lead to formation of a surface layer of (Cd /SUP II/ Fe /SUP II/III/ (CN)/sub 6/) /SUP 2-/1-/ . In the presence of the appropriate cations, this layer was associated with improved cell output parameters. These studies have now been extended to include the n-CdSe system. In this letter we wish to report an unprecedented wavelength dependence of the n-CdSe photoelectrochemical cell.

  19. [Quality management in oncology supported by clinical cancer registries].

    PubMed

    Klinkhammer-Schalke, Monika; Gerken, Michael; Barlag, Hagen; Tillack, Anett

    2015-01-01

    Efforts in nationwide quality management for oncology have so far failed to comprehensively document all levels of care. New organizational structures such as population-based clinical cancer registries or certified organ cancer centers were supposed to solve this problem more sufficiently, but they have to be accompanied by valid trans-sectoral documentation and evaluation of clinical data. To measure feasibility and qualitative effectiveness of guideline implementation we approached this problem with a nationwide investigation from 2000 to 2011. The rate of neoadjuvant radio/chemotherapy in stage UICC II/III rectum cancer, cut-off point 80% for separating good from insufficient quality, was used as a quality indicator. The nationwide analysis indicates an increase from 45% to 70%, but only with the implementation strategy of CME. The combination of new structures, evidence-based quality indicators, organ cancer center and clinical cancer registries has shown good feasibility and seems promising.

  20. All Prime Contract Awards by State or Country, Place, and Contractor. Part 21 (Stafford Virginia-Yellowstone Park)

    DTIC Science & Technology

    1990-01-01

    4 -1Z ..4z .4z .4zzi* -4iiiii* -6 OKI Co H c >- >is > a > a ->-. > >~ CI aOI uro No m af -0 mv) N M W q 0 -or-Go vinsm 10 a-ua. Hv NM 04 00 N 4 --I...i-ain LmI 01@001 sul 0M 00 0000 0 0 0 0 0 00 0 * 4 I06m 0. C.1. 06 .𔃾.4-4-4 06-4 a".00 06 0.-4 06-4 We4 0.0 0lu .4 lo Isla 04 0-4 0 6060600 00* a0

  1. The 5-HT(7) receptor antagonist SB 269970 counteracts restraint stress-induced attenuation of long-term potentiation in rat frontal cortex.

    PubMed

    Tokarski, K; Bobula, B; Kusek, M; Hess, G

    2011-12-01

    The effects of restraint lasting for 10 min, repeated twice daily for 3 days, were studied ex vivo in rat frontal cortex slices prepared 24 h after the last stress session. In slices originating from stressed animals, the amplitude of extracellular field potentials recorded in cortical layer II/III was increased. Stress also resulted in a reduced magnitude of long-term potentiation (LTP) of field potentials. In a separate experimental group, rats were subjected to restraint lasting for 10 min, twice daily for 3 days but, additionally, animals received injections of 5-HT(7) receptor antagonist SB 269970 (1.25 mg/kg) before each restraint stress session. In this group, the amplitude of field potentials and the magnitude of LTP were not different from the control, indicating that stress-induced modifications of basal glutamatergic transmission and synaptic plasticity were prevented by the 5-HT(7) receptor antagonist.

  2. Job Language Performance Requirements for MOS 62B, Construction Equipment Repairer, Reference Soldier’s Manual Dated 13 March 1978.

    DTIC Science & Technology

    1978-03-13

    the backgroun underlying the JLPR. Sections V and VI are the major substantive portions of the analysis. They are the results of the analysis and...Writing 25% II. JOB LANGUAGEp:;O.’ ANCE REQ1R.t"EI;TS TASK: Listen to learn and perform CONDITIONS: Given oral instructions or verbal comm:nds in any...performianc’IIIIi6II 1 ~ I~~ hN 111 S hands-on I,~I I L IIII S demonstratio;III’ I’M ~~=ec~~u~to jI 1,1 ilili II I II 09 i*~ ance difficul? t 11 Ill 11

  3. New species of Lepidocyrtus Bourlet and Entomobrya Rondani (Collembola: Entomobryoidea: Entomobryidae) from Brazil.

    PubMed

    Bellini, Bruno C; Cipola, Nikolas G; Godeiro, Nerivânia N

    2015-10-02

    The taxonomic comprehension of Brazilian entomobryids had several contributions during the last decade, but the absence of detailed chaetotaxic schemes to most of endemic species difficult identifications and probably hides undescribed species in surveys across the country. Herein we describe two new species of the family and provide detailed dorsal chaetotaxy of them, in hope to guide future identifications and descriptions within the genera in Brazil and Neotropical Region. Lepidocyrtus sotoi sp. nov. is possibly more related to L. biphasis due to the lack of antennal and leg scales, but presents a unique dorsal head chaetotaxy among the Neotropical species of the genus. Entomobrya bahiana sp. nov. presents an uncommon color pattern and dorsal chaetotaxy in Th. II-III, Abd. II and IV when compared to other Entomobrya spp. from Neotropical Region.

  4. Progress in corticotropin-releasing factor-1 antagonist development

    PubMed Central

    Zorrilla, Eric P.; Koob, George F.

    2010-01-01

    Corticotropin-releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence suggests the limited efficacy of CRF1 antagonists as antidepressants, CRF1 antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand–receptor interactions for CRF family receptors might yield chemically novel CRF1 receptor antagonists, including peptide CRF1 antagonists, antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF1 antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. PMID:20206287

  5. EVALUATING COSTS WITH UNMEASURED CONFOUNDING: A SENSITIVITY ANALYSIS FOR THE TREATMENT EFFECT

    PubMed Central

    Handorf, Elizabeth A.; Bekelman, Justin E.; Heitjan, Daniel F.; Mitra, Nandita

    2014-01-01

    Estimates of the effects of treatment on cost from observational studies are subject to bias if there are unmeasured confounders. It is therefore advisable in practice to assess the potential magnitude of such biases. We derive a general adjustment formula for loglinear models of mean cost and explore special cases under plausible assumptions about the distribution of the unmeasured confounder. We assess the performance of the adjustment by simulation, in particular, examining robustness to a key assumption of conditional independence between the unmeasured and measured covariates given the treatment indicator. We apply our method to SEER-Medicare cost data for a stage II/III muscle-invasive bladder cancer cohort. We evaluate the costs for radical cystectomy vs. combined radiation/chemotherapy, and find that the significance of the treatment effect is sensitive to plausible unmeasured Bernoulli, Poisson and Gamma confounders. PMID:24587844

  6. A simple technique to achieve bloodless excision of carotid body tumors.

    PubMed

    Spinelli, Francesco; Massara, Mafalda; La Spada, Michele; Stilo, Francesco; Barillà, David; De Caridi, Giovanni

    2014-05-01

    We describe a technique for Shamblin II-III carotid body tumor (CBT) resection to reduce bleeding and neurologic complications during surgery. The technique was based on the fact that CBTs are supplied almost exclusively from the external carotid artery. Therefore, we carefully isolated the origin of the external carotid artery and its distal branches outside the tumor and temporarily clamped all of these vessels after heparin administration. This allowed a safe and bloodless resection as the tumor was dissected from the internal carotid artery in the usual subadventitial plane. The internal carotid artery was never clamped, and respect of peripheral nerves was warranted in the clean and bloodless field. From 2007 to 2010, we treated 11 patients with a CBT: six had a Shamblin II and five had a Shamblin III lesion. Neither perioperative neurologic events nor recurrences occurred after a mean follow-up of 42 months.

  7. ``Blessed rain'' as a drive for the abandonment of ancient settlements along the Israeli coast

    NASA Astrophysics Data System (ADS)

    Ashkenazy, Y.; Faust, A.

    2005-12-01

    Previous studies suggested that arid conditions in the ancient Near-East altered settlement pattern and even triggered the collapse of empires; more humid conditions in the semi-arid Near-East are expected to be more favorite for living. Here we present archaeological evidence for a drastic decline in settlement along the Israeli coast during most of the fifth millennium BP (Early Bronze Age II-III). Based on archaeological and climatic evidence we link this decline to an environment change at that time. We propose that increased precipitation intensified the already existing drainage problems and resulted with flooding, which lead to transformation of arable land into marshes and to spread of diseases, gradually causing settlement decline and abandonment.

  8. Phase I-II clinical trial of Californium-252. Treatment of stage IB carcinoma of the cervix.

    PubMed

    Maruyama, Y; VanNagell, J R; Yoneda, J; Donaldson, E; Gallion, H; Rowley, K; Kryscio, R; Beach, J L

    1987-04-15

    Intracavitary Californium-252 combined with whole-pelvis photon radiotherapy was tested as the sole form of treatment for 22 patients with Stage IB carcinoma of the cervix. Californium-252 (Cf) is a fast neutron-emitting radioisotope currently being tested in trials of neutron brachytherapy (NT). The outcomes of the treated group of patients were traced for local tumor control, survival, patterns of failure, and complications. The Cf intracavitary therapy combined with whole-pelvis photon radiotherapy resulted in 95% 2-year and 91% 5-year actuarial survival. There were 9% Grade II-III complications by the Stockholm scale and 4% local failures. These results were obtained in an early clinical trial with a group of largely poor-risk patients with tumors of mean diameter of 4.3 cm.

  9. Multilocular hydrocephalus: ultrasound studies of origin and development.

    PubMed

    Prats, J M; López-Heredia, J; Gener, B; Freijo, M M; Garaizar, C

    2001-02-01

    Multilocular hydrocephalus is a complication of neonatal hydrocephalus. Its main feature is the presence of multiple cysts inside the ventricles, which requires a specific therapeutic approach. The case of a preterm infant with intracranial hemorrhage grade II-III and central nervous system infection is reported. The cysts developed at the subependymal layer in the posterior area of the patient's thalamus. Their growth and development were charted by ultrasound imaging for several weeks. These types of cysts may grow to occupy the totality of the lateral ventricles, isolating the temporal horns. Of all the reviewed pathogenic mechanisms, we support the hypothesis of an inflammatory vasculitis at the subependymal level, with the subsequent infarct giving rise to the cysts. The osmotic pressure within the cavities, rather than intraventricular fluid, would account for the enlargement of the cysts.

  10. Five-color band ultraviolet photometry of fourteen close binaries

    NASA Technical Reports Server (NTRS)

    Kondo, Y.; Mccluskey, G. E.; Wu, C.-C.

    1981-01-01

    Photometric observations obtained with the Astronomical Netherlands Satellite in five ultraviolet wavelength regions for 14 close binaries are presented. Strong excess far-ultraviolet flux is detected in four objects. The binaries TT Hya, RX Cas, and SX Cas exhibit a pronounced excess of far-ultraviolet flux, which is thought to be the result of mass transfer phenomena in these systems. Observations of the binary R Ara show very peculair variations; its far ultraviolet flux at 1550 A brightened by 0.4 mag between phases 0.7 and 0.8, while its near ultraviolet flux at 3300 A decreased by 0.5 mag over this same half-day interval. The A0 II-III component in the system RZ Sct is seen to dominate the ultraviolet spectrum.

  11. Airland Battle and the Division Artillery Counterfire Dilemma,

    DTIC Science & Technology

    1987-11-30

    ITRRY STUDIESUN A I F J iI36 l NOEhhEE|IIhimI----- i----i---i I’llIIIII 4.’ ....~ - - - -- S -U S.t -. -". ’. . -’.. -’- - -- - ’. _- _ - _ r...celegating part of the counter fire mission to an F .’- a~. . he abilit to mass fires required numerous field artillery D Ar.g’orld A~ar 11, a corps could...envisioned by the -V tle De ense Doctrine. Furthermore, the AirLand Ihattle is not ,itniply a brigade 3 S f ig h t n o r r e a . Cl a i ,i T h r’ t

  12. Application of J-Integral in the Case of a Single Crack in Cantilever Beam

    NASA Astrophysics Data System (ADS)

    Mladensky, Angel S.; Rizov, Victor I.

    2012-12-01

    Mixed mode II/III crack investigation in cantilever bilayered unidirectional fiber reinforced composite beam is reported. The crack is situated between the layers. The two crack arms have different widths. Formula for the strain energy release rate is obtained by the linear elastic fracture mechanics methods using the magnitude of the applied forces, geometrical characteristics of the cross-section, and the elastic moduli of the layers. An equivalent shear modulus of the un-cracked beam portion is used. Several diagrams illustrating the results of parametrical analysis of the strain energy release rate are presented. The paper is a part of a research in the field of fracture behaviour of composite beams.

  13. A novel mutation 3090 G>A of the mitochondrial 16S ribosomal RNA associated with myopathy.

    PubMed

    Coulbault, L; Deslandes, B; Herlicoviez, D; Read, M H; Leporrier, N; Schaeffer, S; Mouadil, A; Lombès, A; Chapon, F; Jauzac, P; Allouche, S

    2007-10-26

    We describe a young woman who presented with a progressive myopathy since the age of 9. Spectrophotometric analysis of the respiratory chain in muscle tissue revealed combined and profound complex I, III, II+III, and IV deficiency ranging from 60% to 95% associated with morphological and histochemical abnormalities of the muscle. An exhaustive screening of mitochondrial transfer and ribosomal RNAs showed a novel G>A substitution at nucleotide position 3090 which was detected only in urine sediment and muscle of the patient and was not found in her mother's blood cells and urine sample. We suggest that this novel de novo mutation in the 16S ribosomal RNA, a nucleotide which is highly conserved in different species, would impair mitochondrial protein synthesis and would cause a severe myopathy.

  14. F-16 Simulator for Man-in-the-Loop Testing of Aircraft Control Systems (SIMTACS).

    DTIC Science & Technology

    1987-12-01

    AD-4199 675 F-16 SIMULA TR FOR MAN-JN-THE- JO TTI M? OF AIRCR"F7 L/2 CONTROL M IS (SjMTAC~ )(U) AHOFQC IN T OFT0 UNCLASSIFIED DE 8 A FJ7CTI 3NCKO7O...OF GNI. 4 HLS 󈧨 - Il1.8 IIIIi .25 1.4 1.6 MICROCOPY RESOLUTION T ES r CHART --- .- u,...,n..nmmnmmna,.,mn mmi ihh’nunan immii u N: 9 It ILL 0...belief in my ability to accomplish this task. Acce slon For t NTIS3 FA&I ti :’ ’,. u " ii jj... W\\i U t At .. .. ..) Page Preface

  15. Structural and microstructural investigation of CdxZn1-xIn2S4 photocatalyst for solar hydrogen production

    NASA Astrophysics Data System (ADS)

    Indrea, E.; Silipaş, D. T.; Bǎnicǎ, R.; Nyari, Terezia; Suciu, Ramona-Crina

    2012-02-01

    A novel low temperature hydrothermal synthesis of II-III2-VI4 (II = Zn, Cd; III = In; VI = S) mixed ternary chalcogenide semiconductors as visible photocatalysts for solar hydrogen production was performed. In this work, an X-ray diffraction based structural and microstructural study of chalcogenide semiconductors type CdxZn1-xIn2S4 (0 ≤ x ≤ 1) is reported. The investigated powder samples were synthesized by a hydrothermal technique, using a Teflon lined closed autoclave with self-generated pressure, at 180°C for 20 hours. Rietveld method based on pseudo-Voigt profile fitting function was applied to perform a simultaneous refinement of X-ray diffraction patterns concerning both material structure and microstructure. The Rietveld refinement of the X-ray diffraction data has been done using the MATCH, MAUD and PowderCel softwares.

  16. Phase I-II clinical trial of Californium-252. Treatment of stage IB carcinoma of the cervix

    SciTech Connect

    Maruyama, Y.; VanNagell, J.R.; Yoneda, J.; Donaldson, E.; Gallion, H.; Rowley, K.; Kryscio, R.; Beach, J.L.

    1987-04-15

    Intracavitary Californium-252 combined with whole-pelvis photon radiotherapy was tested as the sole form of treatment for 22 patients with Stage IB carcinoma of the cervix. Californium-252 (Cf) is a fast neutron-emitting radioisotope currently being tested in trials of neutron brachytherapy (NT). The outcomes of the treated group of patients were traced for local tumor control, survival, patterns of failure, and complications. The Cf intracavitary therapy combined with whole-pelvis photon radiotherapy resulted in 95% 2-year and 91% 5-year actuarial survival. There were 9% Grade II-III complications by the Stockholm scale and 4% local failures. These results were obtained in an early clinical trial with a group of largely poor-risk patients with tumors of mean diameter of 4.3 cm.

  17. Misuse of antimicrobials and selection of methicillin-resistant Staphylococcus pseudintermedius strains in breeding kennels: genetic characterization of bacteria after a two-year interval.

    PubMed

    Rota, A; Milani, C; Corrò, M; Drigo, I; Börjesson, S

    2013-02-01

    Methicillin-resistant Staphylococcus pseudintermedius (MRSP) strains have been isolated from dogs with increasing frequency; prolonged or excessive use of antimicrobials is associated with the selection of MRSP, and misuse of antimicrobials is frequent in breeding kennels. This study was carried out in two breeding kennels (A and B) in which we had isolated MRSP in 2008: the aim was to assess colonization of previously positive bitches and of other bitches sharing the same environment and to assess the genetic profile of both the old and the new strains [spa typing, staphylococcal cassette chromosome mec (SCCmec) typing and Pulsed-field Gel Electrophoresis (PFGE)]. Six animals from Kennel A (two from 2008) and eight from Kennel B (one from 2008) were tested: 16 MRSP strains were isolated only from bitches housed in Kennel B. Old and new isolates were mecA positive, resulted spa type t02 and carried SSCmec II-III. PGFE showed that all isolates were related and belonged to the main clone lineage dominating in Europe, ST71-J-t02-II-III. Kennels A and B differ in the use of antimicrobials, which has been reduced over time in Kennel A, while has remained excessive in Kennel B, where many agents belonging to different classes (third-generation cephalosporins, fluoroquinolones, macrolids) are administered to dogs, without veterinary supervision, especially around parturition. Misuse of antimicrobials is the key factor for the selection of MRSP strains in healthy dogs and for their persistence over time. Dog breeders should be aware that infections caused by multiresistant bacteria have very limited therapeutical options and represent a huge challenge for animal health.

  18. In vivo labeling of parvalbumin-positive interneurons and analysis of electrical coupling in identified neurons.

    PubMed

    Meyer, Axel H; Katona, István; Blatow, Maria; Rozov, Andrei; Monyer, Hannah

    2002-08-15

    GABAergic interneurons can pace the activity of principal cells and are thus critically involved in the generation of oscillatory and synchronous network activity. The specific role of various GABAergic subpopulations, however, has remained elusive. This is in part attributable to the scarcity of certain GABAergic neurons and the difficulty of identifying them in slices obtained from brain regions in which anatomical structures are not readily recognizable in the live preparation. To facilitate the functional analysis of GABAergic interneurons, we generated transgenic mice in which the enhanced green fluorescent protein (EGFP) was specifically expressed in parvalbumin-positive neurons. The high fidelity of expression obtained using bacterial artificial chromosome transgenes resulted in EGFP-labeled neurons in nearly all brain regions known to contain parvalbumin-expressing neurons. Immunocytochemical analysis showed that EGFP expression was primarily restricted to parvalbumin-positive cells. In addition to cell body labeling, EGFP expression was high enough in many neurons to enable the visualization of dendritic structures. With the help of these mice, we investigated the presence of electrical coupling between parvalbumin-positive cells in brain slices obtained from young and adult animals. In dentate gyrus basket cells, electrical coupling was found in slices from young [postnatal day 14 (P14)] and adult (P28 and P42) animals, but both strength and incidence of coupling decreased during development. However, electrical coupling between parvalbumin-positive multipolar cells in layer II/III of the neocortex remains unaltered during development. Yet another developmental profile of electrical coupling was found between layer II/III parvalbumin-positive cells and excitatory principal cells. Between these neurons, electrical coupling was found at P14 but not at P28. The results indicate that the presence and strength of electrical coupling is developmentally

  19. Human epidermal growth factor receptor 2/neu protein expression in meningiomas: An immunohistochemical study

    PubMed Central

    Telugu, Ramesh Babu; Chowhan, Amit Kumar; Rukmangadha, Nandyala; Patnayak, Rashmi; Phaneendra, Bobbidi Venkata; Prasad, Bodapati Chandra Mowliswara; Reddy, Mandyam Kumaraswamy

    2016-01-01

    Background: Meningiomas are common slow-growing primary central nervous system tumors that arise from the meningothelial cells of the arachnoid and spinal cord. Human epidermal growth factor receptor 2 (HER2) or HER2/neu (also known as c-erbB2) is a 185-kD transmembrane glycoprotein with tyrosine kinase activity expressed in meningiomas and various other tumors. It can be used in targeted therapy for HER2/neu positive meningiomas. Aim: To correlate the expression of HER2/neu protein in meningiomas with gender, location, histological subtypes, and grade. Materials and Methods: It was 3½ years prospective (March 2010–October 2011) and retrospective (May 2008–February 2010) study of histopathologically diagnosed intracranial and intraspinal meningiomas. Clinical details of all the cases were noted from the computerized hospital information system. Immunohistochemistry for HER2/neu protein was performed along with scoring. Statistical analysis was done using Chi-square test to look for any association of HER2/neu with gender, location, grade, and various histological subtypes of meningiomas at 5% level of significance. Results: A total of 100 cases of meningiomas were found during the study period. Of which, 80 were Grade I, 18 were Grade II, and 2 were Grade III meningiomas as per the World Health Organization 2007 criteria. The female-male ratio was 1.9:1 and the mean age was 47.8 years. HER2/neu protein was expressed in 75% of Grade I and 72.2% of Grade II and none of Grade III meningiomas. About 72.7% brain invasive meningiomas showed HER2/neu immunopositivity. Conclusion: HER2/neu protein was expressed in 73% of meningiomas. Statistically significant difference of HER2/neu expression was not seen between females and males of Grade I and Grade II/III meningiomas, intracranial and spinal tumors, Grade I and Grade II/III cases, and various histological subtypes of meningiomas. PMID:27695231

  20. Nutritional predictors for postoperative short-term and long-term outcomes of patients with gastric cancer

    PubMed Central

    Kanda, Mitsuro; Mizuno, Akira; Tanaka, Chie; Kobayashi, Daisuke; Fujiwara, Michitaka; Iwata, Naoki; Hayashi, Masamichi; Yamada, Suguru; Nakayama, Goro; Fujii, Tsutomu; Sugimoto, Hiroyuki; Koike, Masahiko; Takami, Hideki; Niwa, Yukiko; Murotani, Kenta; Kodera, Yasuhiro

    2016-01-01

    Abstract Evidence indicates that impaired immunocompetence and nutritional status adversely affect short-term and long-term outcomes of patients with cancer. We aimed to evaluate the clinical significance of preoperative immunocompetence and nutritional status according to Onodera's prognostic nutrition index (PNI) among patients who underwent curative gastrectomy for gastric cancer (GC). This study included 260 patients with stage II/III GC who underwent R0 resection. The predictive values of preoperative nutritional status for postoperative outcome (morbidity and prognosis) were evaluated. Onodera's PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × lymphocyte count (per mm3). The mean preoperative PNI was 47.8. The area under the curve for predicting complications was greater for PNI compared with the serum albumin concentration or lymphocyte count. Multivariate analysis identified preoperative PNI < 47 as an independent predictor of postoperative morbidity. Moreover, patients in the PNI < 47 group experienced significantly shorter overall and disease-free survival compared with those in the PNI ≥ 47 group, notably because of a higher prevalence of hematogenous metastasis as the initial recurrence. Subgroup analysis according to disease stage and postoperative adjuvant treatment revealed that the prognostic significance of PNI was more apparent in patients with stage II GC and in those who received adjuvant chemotherapy. Preoperative PNI is easy and inexpensive to determine, and our findings indicate that PNI served as a significant predictor of postoperative morbidity, prognosis, and recurrence patterns of patients with stage II/III GC. PMID:27310954

  1. Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease.

    PubMed

    Takeda, Takahiro; Uchihara, Toshiki; Arai, Nobutaka; Mizutani, Toshio; Iwata, Makoto

    2009-01-01

    The hippocampal involvement in amyotrophic lateral sclerosis (ALS) patients has been known for more than a decade, however, its relationship to clinical manifestations including memory deficits and topographical differentiation from Alzheimer disease (AD) remain unclear. In order to clarify the anatomopathological features in the hippocampus and their relevance to disease-specific memory deficits in ALS patients, topography and cytopathology of the hippocampal lesions along the perforant pathway were quantitatively and semiquantitatively surveyed in 14 ALS patients with extramotor involvement. These pathological findings were compared with clinical characteristics assessed from their clinical records. Cytoplasmic inclusions initially appear in the granular cells of the dentate gyrus (DG) and superficial small neurons of the transentorhinal cortex (TEC) with mild subicular degeneration (stage I: inclusion stage). Subsequent gliosis and neuronal loss of the TEC, concomitant with presynaptic degeneration of the outer molecular layer of the DG, suggests an extension of the degeneration through the perforant pathway (stage II: early perforant stage). In a more advanced stage, the presynaptic degeneration is more evident with moderate to severe neuronal loss in the TEC (stage III: advanced perforant stage). This advanced stage was associated with episodic memory deficits mimicking AD in some ALS patients. This ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II-III of the TEC is different from neurofibrillary tangles of AD, dominant in layer II-III of the entorhinal cortex. Because this involvement of the TEC-molecular DG projection and subiculum is specific to ALS, it will provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of AD.

  2. A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer’s Disease

    PubMed Central

    Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

    2016-01-01

    One century after its first description, pathology of Alzheimer’s disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD

  3. Respiratory burst in alveolar macrophages exposed to urban particles is not a predictor of cytotoxicity.

    PubMed

    Breznan, Dalibor; Goegan, Patrick; Chauhan, Vinita; Karthikeyan, Subramanian; Kumarathasan, Prem; Cakmak, Sabit; Nadeau, Denis; Brook, Jeffrey R; Vincent, Renaud

    2013-06-01

    We examined the utility of respiratory burst measurements in alveolar macrophages to assess adverse cellular changes following exposure to urban particles. Cells were obtained by bronchioalveolar lavage of Fisher 344 rats and exposed (0-100 μg/well) to urban particles (EHC-93, SRM-1648, SRM-1649, PM2.5), the soluble (EHC-93sol) and insoluble (EHC-93insol) fractions of EHC-93 (EHC-93tot), mineral particles (TiO(2), SiO(2)) and metal oxides (iron III oxide, iron II/III oxide, copper II oxide, nickel II oxide). The particle-induced respiratory burst was measured by chemiluminescence for 2h after the addition of particles. The cells were then stimulated with phorbol 12-myristate 13-acetate (PMA), yeast Zymosan fragments (Zymosan), or lipopolysaccharide plus interferon-gamma (LPS/IFN-γ) and the stimulant-induced respiratory burst was measured. Independently of the potential of particles to induce directly a respiratory burst, exposure to most particles attenuated the subsequent stimulant-induced burst. The notable exception was SiO(2), which produced a strong respiratory burst upon contact with the macrophages and enhanced the subsequent response to PMA or LPS/IFN-γ. Based on the degree of inhibition of the stimulant-dependent respiratory burst, particles were clustered into groups of high (SRM-1649, iron III oxide), intermediate (EHC-93tot, EHC-93insol, SRM-1648, VERP, iron II/III oxide, copper II oxide), and low (EHC-93sol, SiO(2), TiO2 and nickel II oxide) potency. Across these clusters, the potency of the particles to inhibit the stimulant-dependent respiratory burst showed poor correlation with cytotoxicity determined by XTT reduction assay.

  4. Effects of High-Intensity Interval Training versus Continuous Training on Physical Fitness, Cardiovascular Function and Quality of Life in Heart Failure Patients

    PubMed Central

    Benda, Nathalie M. M.; Seeger, Joost P. H.; Stevens, Guus G. C. F.; Hijmans-Kersten, Bregina T. P.; van Dijk, Arie P. J.; Bellersen, Louise; Lamfers, Evert J. P.; Hopman, Maria T. E.; Thijssen, Dick H. J.

    2015-01-01

    Introduction Physical fitness is an important prognostic factor in heart failure (HF). To improve fitness, different types of exercise have been explored, with recent focus on high-intensity interval training (HIT). We comprehensively compared effects of HIT versus continuous training (CT) in HF patients NYHA II-III on physical fitness, cardiovascular function and structure, and quality of life, and hypothesize that HIT leads to superior improvements compared to CT. Methods Twenty HF patients (male:female 19:1, 64±8 yrs, ejection fraction 38±6%) were allocated to 12-weeks of HIT (10*1-minute at 90% maximal workload—alternated by 2.5 minutes at 30% maximal workload) or CT (30 minutes at 60–75% of maximal workload). Before and after intervention, we examined physical fitness (incremental cycling test), cardiac function and structure (echocardiography), vascular function and structure (ultrasound) and quality of life (SF-36, Minnesota living with HF questionnaire (MLHFQ)). Results Training improved maximal workload, peak oxygen uptake (VO2peak) related to the predicted VO2peak, oxygen uptake at the anaerobic threshold, and maximal oxygen pulse (all P<0.05), whilst no differences were present between HIT and CT (N.S.). We found no major changes in resting cardiovascular function and structure. SF-36 physical function score improved after training (P<0.05), whilst SF-36 total score and MLHFQ did not change after training (N.S.). Conclusion Training induced significant improvements in parameters of physical fitness, although no evidence for superiority of HIT over CT was demonstrated. No major effect of training was found on cardiovascular structure and function or quality of life in HF patients NYHA II-III. Trial Registration Nederlands Trial Register NTR3671 PMID:26517867

  5. Influence of solvent on the spectroscopic properties of cyano complexes of ruthenium(II)

    SciTech Connect

    Timpson, C.J.; Meyer, J.M.; Bignozzi, C.A.; Sullivan, P.B.; Kober, E.M.

    1996-02-22

    Specific solute-solvent interactions are known to play an important role in optical and thermal electron transfer involving transition-metal complexes. These interactions can influence both spectroscopic energies and redox potentials in a significant way. Their existence has been documented in the literature, and qualitative models have been proposed, but they have yet to be examined quantitatively. Literature examples include mixed cyano-pyridyl complexes of Fe(II) and Ru(II) where specific interactions occur with the cyanide ligands. We extend that work here and report the effect of solvent on absorption, emission, and Ru{sup III/II} reduction potentials in the series cis-[Ru(bpy){sub 2}(py)(CN)]{sup +}, cis-Ru(bpy){sub 2}(CN){sub 2}, [Ru(tpy)(CN){sub 3}]{sup -}, [Ru(bpy)(CN){sub 4}]{sup 2-}, and [Ru(MQ{sup +})(CN){sub 5}]{sup 2-}, where there is a sequential increase in the number of cyanide ligands. The goals were to obtain systematic data on specific solvent effects in these complexes, to analyze the effects, and to develop models to explain them. UV-visible spectra, emission spectra, and Ru{sup III/II} reduction potentials have been measured. The shifts in the metal-to-ligand charge transfer (MLCT) absorption (E{sub abs}) or emission (E{sub em}) band energies with solvent increase linearly with the number of cyano ligands and correlate well with the Gutmann `acceptor number` of the solvent. 32 refs., 8 figs., 4 tabs.

  6. HCV antibody response and genotype distribution in different areas and races of China.

    PubMed

    Jia, Leili; Yu, Jiyun; Yang, Jinliang; Song, Hongbin; Liu, Xuelin; Wang, Yong; Xu, Yuanyong; Zhang, Chuanfu; Zhong, Yanwei; Li, Qiao

    2009-06-13

    Hepatitis C virus (HCV) heterogeneity accounts for the failure of effective vaccine development and the lack of successful anti-viral therapy in some patients. Little is known about the immune response to HCV peptides and the region or race specific genotypes in China. The objective of this study was to characterize HCV antibody immune response to HCV peptides and HCV genotypes in different regions and races of China. A total of 363 serum samples were collected from HCV carriers in 6 regions in China. The immune response to HCV peptides was evaluated by ELISA. HCV genotypes were examined using nested RT-PCR. We found that the anti-HCV antibody neutralization rates were significantly different among the serum samples from different areas or from different races in the same area. For samples from Tibet and Sinkiang, the rates of neutralization by HCV peptides were only 3.2% and 30.8%, respectively. The genotypes of samples from Tibet and Sinkiang were apparently heterogeneic and included type I, II, III and multiple types (I/II/III, I/II, I/III, II/III). One specific sample with multiple-genotype (I/II/III) HCV infection was found to consist of type I, II, III, II/III and an unclassified genotype. These studies indicate that the anti-HCV antibody immune response to HCV peptides varied across regions and among races. The distribution of HCV genotypes among Tibetans in Tibet and Uighurs in Sinkiang was different from that in the inner areas of China. In addition, a "master" genotype, type II, was found to exist in HCV infection with multiple HCV genotypes.

  7. Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs.

    PubMed

    Ellsworth, Katarzyna A; Pollard, Laura M; Cathey, Sara; Wood, Tim

    2016-07-28

    Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.

  8. Nutritional predictors for postoperative short-term and long-term outcomes of patients with gastric cancer.

    PubMed

    Kanda, Mitsuro; Mizuno, Akira; Tanaka, Chie; Kobayashi, Daisuke; Fujiwara, Michitaka; Iwata, Naoki; Hayashi, Masamichi; Yamada, Suguru; Nakayama, Goro; Fujii, Tsutomu; Sugimoto, Hiroyuki; Koike, Masahiko; Takami, Hideki; Niwa, Yukiko; Murotani, Kenta; Kodera, Yasuhiro

    2016-06-01

    Evidence indicates that impaired immunocompetence and nutritional status adversely affect short-term and long-term outcomes of patients with cancer. We aimed to evaluate the clinical significance of preoperative immunocompetence and nutritional status according to Onodera's prognostic nutrition index (PNI) among patients who underwent curative gastrectomy for gastric cancer (GC).This study included 260 patients with stage II/III GC who underwent R0 resection. The predictive values of preoperative nutritional status for postoperative outcome (morbidity and prognosis) were evaluated. Onodera's PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × lymphocyte count (per mm).The mean preoperative PNI was 47.8. The area under the curve for predicting complications was greater for PNI compared with the serum albumin concentration or lymphocyte count. Multivariate analysis identified preoperative PNI < 47 as an independent predictor of postoperative morbidity. Moreover, patients in the PNI < 47 group experienced significantly shorter overall and disease-free survival compared with those in the PNI ≥ 47 group, notably because of a higher prevalence of hematogenous metastasis as the initial recurrence. Subgroup analysis according to disease stage and postoperative adjuvant treatment revealed that the prognostic significance of PNI was more apparent in patients with stage II GC and in those who received adjuvant chemotherapy.Preoperative PNI is easy and inexpensive to determine, and our findings indicate that PNI served as a significant predictor of postoperative morbidity, prognosis, and recurrence patterns of patients with stage II/III GC.

  9. Adenocarcinoma of the Esophagogastric Junction: The Pattern of Metastatic Lymph Node Dissemination as a Rationale for Elective Lymphatic Target Volume Definition

    SciTech Connect

    Meier, Iris; Merkel, Susanne; Papadopoulos, Thomas; Sauer, Rolf; Hohenberger, Werner; Brunner, Thomas B.

    2008-04-01

    Purpose: Regional nodal metastasis after neoadjuvant chemoradiation of adenocarcinoma of the esophagogastric junction (AEG) predicts survival. We aimed to clarify the lymph node (LN) distribution of AEG according to location of the tumor mass and invasion of neighboring areas for the selection of radiotherapy planning target volume (PTV) margins. Methods and Materials: Patterns of regional spread were analyzed in pathology reports of 326 patients patients with AEG who had undergone primary resection, with {>=}15 lymph nodes examined. Tumors were classified into AEG types based on endoscopy and pathology reports. Fisher's exact test was used to compare nodal disease and tumor characteristics. Pulmonary dose-volume histograms were tested in 8 patients. Results: Nodes were positive in 81% of T2 to T4 tumors. Type of AEG, tumor size, lymphovascular invasion, and grading significantly influenced nodal distribution. We found that marked esophageal invasion of AEG II/III significantly correlated with paraesophageal nodal disease, and T3 to T4 AEG II/III had a significant rate of splenic hilum/artery nodes. Middle and lower paraesophageal nodes should be treated in T2 to T4 AEG I and AEG II with {>=}15 mm involvement above the Z-line, and T3 to T4 AEG II. The splenic hilum and artery nodes can be spared in T2 AEG tumors, especially Type I tumors. The influence of paraesophageal nodal treatment on the risk of postoperative pulmonary complications can be estimated from dose-volume histograms. Conclusions: Accurate pretherapeutic staging predicts the risk of subclinical nodal disease and should be used to select the appropriate radiotherapeutic PTV. Careful selection of the PTV can be used to maximize the therapeutic window in multimodal therapy for AEG.

  10. Elevated level of HSPA1L mRNA correlates with graft-versus-host disease.

    PubMed

    Atarod, Sadaf; Turner, Brie; Pearce, Kim Frances; Ahmed, Shaheda S; Norden, Jean; Bogunia-Kubik, Katarzyna; Wang, Xiao-nong; Collin, Matthew; Dickinson, Anne Mary

    2015-06-01

    Graft-versus-host disease (GVHD) can be a fatal complication of allogeneic stem cell transplantation (allo-HSCT). GVHD can be classified as acute (aGVHD: up to 100 days) or chronic (cGVHD: after 100 days) based on the time-point of disease occurrence. At present there are a limited number of biomarkers available for use in the clinic. Thus, the aim of this research was to evaluate the biomarker potential of the extensively studied Heat Shock Protein 70 family members (HSPA1A/HSPA1B and HSPA1L) at the messenger RNA (mRNA) level in acute and cGVHD patient cohorts. In the skin biopsies, HSPA1L mRNA expression was lower in patients with severe aGVHD (grades II-III) when compared to those with none or low grade aGVHD (grades 0-I) and normal controls. In whole blood, HSPA1L mRNA expression level was significantly (p = 0.008) up-regulated at 28 days post-transplant in cGVHD patients with a significant area under the curve (AUC = 0.773). In addition, HSPA1B expression in whole blood was significantly higher at 3 months post-transplant in both the aGVHD grade II-III (p = 0.012) and cGVHD (p = 0.027) patients. Our initial results in this small cohort show that quantifying HSPA1L mRNA expression in the whole blood of allo-HSCT patients at day 28 post-allo-HSCT may be a useful predictive biomarker for cGVHD.

  11. Patterns of Care and Outcomes of Adjuvant Radiotherapy for Meningiomas: A Surveillance, Epidemiology, and End Results and Medicare Linked Analysis

    PubMed Central

    Ugiliweneza, Beatrice; Burton, Eric; Skirboll, Stephen; Woo, Shiao; Boakye, Max

    2016-01-01

    Background: The role of adjuvant stereotactic radiosurgery (SRS) and fractionated radiotherapy (XRT) are unknown in patients with resected meningiomas. Objective: To identify patterns of care and outcomes of adjuvant radiotherapy for meningiomas in the Linked Surveillance, Epidemiology, and End Results (SEER) Medicare data. Methods: A total of 1,964 patients older than 66 years included in the SEER-Medicare data, who were diagnosed with meningioma, and underwent craniotomy were included for analysis. Results: Patients were less likely to receive adjuvant therapy if they were older than 75 (OR 0.730, 95% CI 0.548-0.973), female sex (OR 0.731, 95% CI 0.547-0.978), or unmarried (OR 0.692, 95% CI 0.515-0.929). Patients were more likely to receive adjuvant treatment for Grade II/III tumors (OR 5.586, 95% CI 2.135-13.589), tumors over 5 cm (OR 1.850, 95% CI 1.332-2.567), or partial resection (OR 3.230, 95% CI 2.327-4.484). Yearly between 2000 and 2009, 10.65 – 19.77% of patients received adjuvant therapy. Although no survival benefit was seen with the addition of adjuvant therapy (p = 0.1236), the subgroup of patients receiving SRS had a decreased risk of death compared to those receiving surgery alone (aHR 0.544, 95% CI 0.318 – 0.929). Conclusion: Utilization of adjuvant XRT and SRS remained stable between 2000 and 2010. Male sex, young age, marriage, partial resection, Grade II/III tumors, and large tumors predicted the use of adjuvant therapy. For all patients, SRS decreased the risk of death compared to craniotomy alone. PMID:27186449

  12. En bloc excision and autogenous fibular reconstruction for aggressive giant cell tumor of distal radius: a report of 12 cases and review of literature

    PubMed Central

    2011-01-01

    Introduction Giant cell tumor (GCT) of distal radius follows a comparatively aggressive behaviour. Wide excision is the management of choice, but this creates a defect at the distal end of radius. The preffered modalities for reconstruction of such a defect include vascularized/non-vascularized bone graft, osteoarticular allografts and custom-made prosthesis. We here present our experience with wide resection and non-vascularised autogenous fibula grafting for GCT of distal radius. Materials and methods Twelve patients with a mean age of 34.7 years (21-43 years) with Campanacci Grade II/III GCT of distal radius were managed with wide excision of tumor and reconstruction with ipsilateral nonvascularised fibula, fixed with small fragment plate to the remnant of the radius. Primary autogenous iliac crest grafting was done at the fibuloradial junction in all the patients. Results Mean follow up period was 5.8 years (8.2-3.7 years). Average time for union at fibuloradial junction was 33 weeks (14-69 weeks). Mean grip strength of involved side was 71% (42-86%). The average range of movements were 52° forearm supination, 37° forearm pronation, 42° of wrist palmerflexion and 31° of wrist dorsiflexion with combined movements of 162°. Overall revised musculoskeletal tumor society (MSTS) score averaged 91.38% (76.67-93.33%) with five excellent, four good and three satisfactory results. There were no cases with graft related complications or deep infections, 3 cases with wrist subluxation, 2 cases with non union (which subsequently united with bone grafting) and 1 case of tumor recurrence. Conclusion Although complication rate is high, autogenous non-vascularised fibular autograft reconstruction of distal radius can be considered as a reasonable option after en bloc excision of Grade II/III GCT. PMID:21385393

  13. The origin of oil in the Cretaceous succession from the South Pars Oil Layer of the Persian Gulf

    NASA Astrophysics Data System (ADS)

    Rahmani, Omeid; Aali, Jafar; Junin, Radzuan; Mohseni, Hassan; Padmanabhan, Eswaran; Azdarpour, Amin; Zarza, Sahar; Moayyed, Mohsen; Ghazanfari, Parviz

    2013-07-01

    The origin of the oil in Barremian-Hauterivian and Albian age source rock samples from two oil wells (SPO-2 and SPO-3) in the South Pars oil field has been investigated by analyzing the quantity of total organic carbon (TOC) and thermal maturity of organic matter (OM). The source rocks were found in the interval 1,000-1,044 m for the Kazhdumi Formation (Albian) and 1,157-1,230 m for the Gadvan Formation (Barremian-Hauterivian). Elemental analysis was carried out on 36 samples from the source rock candidates (Gadvan and Kazhdumi formations) of the Cretaceous succession of the South Pars Oil Layer (SPOL). This analysis indicated that the OM of the Barremian-Hauterivian and Albian samples in the SPOL was composed of kerogen Types II and II-III, respectively. The average TOC of analyzed samples is less than 1 wt%, suggesting that the Cretaceous source rocks are poor hydrocarbon (HC) producers. Thermal maturity and Ro values revealed that more than 90 % of oil samples are immature. The source of the analyzed samples taken from Gadvan and Kazhdumi formations most likely contained a content high in mixed plant and marine algal OM deposited under oxic to suboxic bottom water conditions. The Pristane/nC17 versus Phytane/nC18 diagram showed Type II-III kerogen of mixture environments for source rock samples from the SPOL. Burial history modeling indicates that at the end of the Cretaceous time, pre-Permian sediments remained immature in the Qatar Arch. Therefore, lateral migration of HC from the nearby Cretaceous source rock kitchens toward the north and south of the Qatar Arch is the most probable origin for the significant oils in the SPOL.

  14. Emission lines in the optical spectrum of 3 Cen A

    NASA Astrophysics Data System (ADS)

    Wahlgren, G. M.; Hubrig, S.

    2004-05-01

    Previously, weak emission lines had been detected at red wavelengths in the spectra of a limited sample of mid to late B type main sequence stars. A fuller description of the occurrence and origins of these lines has yet to be forwarded, in part due to the lack of observations detailing the spectral transitions involved. To address this deficiency, we present a line list of weak emission features found in the optical and near infrared spectral region of the chemically peculiar He-weak star 3 Cen A (HD 120709). Nearly 350 features, mostly associated with allowed transitions from high-excitation states of first ions, are catalogued along with identifications. Prominent among the emission lines are the spectra P II, Mn II, Fe II, Ni II and Cu II. Emission lines from Ca II, Si II and Hg II are also evident. Abundances are determined for several elements from synthetic spectrum fitting, with anomalies detected for the ions O I/II, P II/III and Si II/III. The LTE synthetic spectrum fitting also revealed that the low excitation 4s-4p transitions of Fe II predict an abundance that is greater than that determined from higher excitation 4d-4f transitions. Several of these latter transitions have upper energy levels that are found to be associated with emission lines. We also present empirical considerations for the excitation processes leading to the weak emission lines. Based on observations obtained at the European Southern Observatory, La Silla, Chile, No. 65.L-0316 and Paranal, Chile No. 266.D-5655. Tables 2 and 3 are only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/418/1073

  15. Delayed-type hypersensitivity (DTH) immune response related with EBV-DNA in nasopharyngeal carcinoma treated with autologous dendritic cell vaccination after radiotherapy.

    PubMed

    Li, Feng; Song, Dan; Lu, Yue; Zhu, Huanfeng; Chen, Zhenzhang; He, Xia

    2013-04-01

    The aim of this work was to investigate the outcome of an autologous dendritic cell (DC) vaccination in patients with stage II/III nasopharyngeal carcinomas (NPC). From 38 patients with stage II/III Epstein-Barr virus (EBV)-associated NPCs after a radiotherapy, 16 human leukocyte antigen-A2 (HLA-A2)-positive patients were enrolled and medicated with autologous DCs, which were pulsed with HLA-A2-restricted EBV-encoded latent membrane protein 2A (LMP2A) peptides. The lymphocyte subsets, serum cytokines, and EBV-DNA levels as well as the delayed-type hypersensitivity (DTH) responses were determined after vaccination combined with a radiotherapy/chemotherapy. The serum levels of interleukin-2 and interferon-γ (P<0.05) as well as the percentage of natural killer and CD4+T cells increased significantly (P<0.05) after the vaccination. Nine of 16 (56.25%) patients showed a positive skin response to the HLA-A2 restricted EBV LMP2A peptides in a DTH test. The serum EBV-DNA level decreased significantly from 1519 ± 384 to 1214 ± 211 copies/mL in the 9 DTH-positive patients (P=0.0310). No unanticipated or serious toxicity was observed and the vaccine was well tolerated. In conclusion, in NPC patients vaccinated after radiotherapy with autologous DCs, which were pulsed with EBV LMP2A peptides, Th1-specific immune responses were elicited particularly in DTH test positive individuals. The clinical results obtained are encouraging and the EBV-specific HLA-A2-restricted DC vaccination is a promising treatment for EBV-related NPCs.

  16. A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

    PubMed Central

    2010-01-01

    Background Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. Methods We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood. Results Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009). Conclusions Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients. PMID:20144226

  17. Healthcare-associated, community-acquired and hospital-acquired bacteraemic urinary tract infections in hospitalized patients: a prospective multicentre cohort study in the era of antimicrobial resistance.

    PubMed

    Horcajada, J P; Shaw, E; Padilla, B; Pintado, V; Calbo, E; Benito, N; Gamallo, R; Gozalo, M; Rodríguez-Baño, J

    2013-10-01

    The clinical and microbiological characteristics of community-onset healthcare-associated (HCA) bacteraemia of urinary source are not well defined. We conducted a prospective cohort study at eight tertiary-care hospitals in Spain, from October 2010 to June 2011. All consecutive adult patients hospitalized with bacteraemic urinary tract infection (BUTI) were included. HCA-BUTI episodes were compared with community-acquired (CA) and hospital-acquired (HA) BUTI. A logistic regression analysis was performed to identify 30-day mortality risk factors. We included 667 episodes of BUTI (246 HCA, 279 CA and 142 HA). Differences between HCA-BUTI and CA-BUTI were female gender (40% vs 69%, p <0.001), McCabe score II-III (48% vs 14%, p <0.001), Pitt score ≥2 (40% vs 31%, p 0.03), isolation of extended spectrum β-lactamase-producing Enterobacteriaciae (13% vs 5%, p <0.001), median hospital stay (9 vs 7 days, p 0.03), inappropriate empirical antimicrobial therapy (21% vs 13%, p 0.02) and mortality (11.4% vs 3.9%, p 0.001). Pseudomonas aeruginosa was more frequently isolated in HA-BUTI (16%) than in HCA-BUTI (4%, p <0.001). Independent factors for mortality were age (OR 1.04; 95% CI 1.01-1.07), McCabe score II-III (OR 3.2; 95% CI 1.8-5.5), Pitt score ≥2 (OR 3.2 (1.8-5.5) and HA-BUTI OR 3.4 (1.2-9.0)). Patients with HCA-BUTI are a specific group with significant clinical and microbiological differences from patients with CA-BUTI, and some similarities with patients with HA-BUTI. Mortality was associated with patient condition, the severity of infection and hospital acquisition.

  18. Selection of individual VH genes occurs at the pro-B to pre-B cell transition*

    PubMed Central

    Meng, Wenzhao; Yunk, Lenka; Wang, Li-San; Maganty, Avinash; Xue, Emily; Cohen, Philip L.; Eisenberg, Robert A.; Weigert, Martin G.; Mancini, Stephane J.C.; Luning Prak, Eline T.

    2011-01-01

    B cells are subjected to selection at multiple checkpoints during their development. The selection of antibody heavy chains is difficult to study because of the large diversity of the CDR3. In order to study the selection of individual antibody heavy chain variable region genes (VH), we performed CDR3 spectratyping of 75–300 rearrangements per individual VH in C57BL6/J mice. We measured the fraction of rearrangements that were in-frame (IF fraction) in B cell DNA. We demonstrate that individual VH genes have different IF fractions, ranging from 10% to 90%, and that these IF fractions are reproducible in different mice. For most VHs, the IF fraction in pro-B cells approximated 33% and then shifted to the nearly final (mature) B cell value by the cycling pre-B cell stage. The frequency of high IF VH usage increased in cycling pre-B cells compared to pro-B cells, whereas this did not occur for low IF VHs. The IF fraction did not shift as much in BCR-expressing B cells and was minimally affected by light chain usage for most VH. High IF clan II/III VHs share more positively charged CDR2 sequences, whereas high IF clan I J558 CDR2 sequences are diverse. These data indicate that individual VHs are subjected to differential selection, that VH IF fraction is mainly established through pre-BCR mediated selection, that it may operate differently in clan I vs. II/III VHs, and that it has a lasting influence on the antibody repertoire. PMID:21746964

  19. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury.

    PubMed

    Patil, Naeem K; Parajuli, Nirmala; MacMillan-Crow, Lee Ann; Mayeux, Philip R

    2014-04-01

    Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI.

  20. Effects of prenatal irradiation on the development of cerebral cortex and corpus callosum of the mouse

    SciTech Connect

    Schmidt, S.L.; Lent, R.

    1987-10-08

    Defects of the cerebral cortex and corpus callosum of mice subjected prenatally to gamma irradiation were evaluated as a function of dose and of embryonic age at irradiation. Pregnant mice were exposed to a gamma source at 16, 17, and 19 days of gestation (E16, E17, and E19, respectively), with total doses of 2 Gy and 3 Gy, in order to produce brain defects on their progeny. At 60 postnatal days, the brains of the offspring were analyzed qualitatively and quantitatively and compared with those of nonirradiated animals. Mice irradiated at E16 were all acallosal. Those that were exposed to 2 Gy displayed an aberrant longitudinal bundle typical of other acallosals, but this was not the case in those irradiated with 3 Gy. The corpus callosum of animals irradiated at E17 with 3 Gy was pronouncedly hypotrophic, but milder effects were observed in the other groups. Quantitative analysis confirmed a dependence of callosal midsagittal area upon dose and age at irradiation, and, in addition, indicated an interaction between these variables. The neocortex of irradiated animals was hypotrophic: layers II-III were much more affected than layer V, and this was more affected than layer VI. Quantitative analysis indicated that this effect also depended on dose and age at irradiation and that it was due to a loss of cortical neurons. Furthermore, a positive correlation was found between the number of neurons within layers II-III, and V and the midsagittal area of the corpus callosum. Ectopic neurons were found in the white matter and in layer I of animals irradiated at E16 and E17, indicating that fetal exposure to ionizing radiation interfered with the migration of cortical neuroblasts.

  1. Adaptive Randomization of Neratinib in Early Breast Cancer

    PubMed Central

    Park, John W.; Liu, Minetta C.; Yee, Douglas; Yau, Christina; van 't Veer, Laura J.; Symmans, W. Fraser; Paoloni, Melissa; Perlmutter, Jane; Hylton, Nola M.; Hogarth, Michael; DeMichele, Angela; Buxton, Meredith B.; Chien, A. Jo; Wallace, Anne M.; Boughey, Judy C.; Haddad, Tufia C.; Chui, Stephen Y.; Kemmer, Kathleen A.; Kaplan, Henry G.; Liu, Minetta C.; Isaacs, Claudine; Nanda, Rita; Tripathy, Debasish; Albain, Kathy S.; Edmiston, Kirsten K.; Elias, Anthony D.; Northfelt, Donald W.; Pusztai, Lajos; Moulder, Stacy L.; Lang, Julie E.; Viscusi, Rebecca K.; Euhus, David M.; Haley, Barbara B.; Khan, Qamar J.; Wood, William C.; Melisko, Michelle; Schwab, Richard; Lyandres, Julia; Davis, Sarah E.; Hirst, Gillian L.; Sanil, Ashish; Esserman, Laura J.; Berry, Donald A.

    2017-01-01

    Background I-SPY2, a standing, multicenter, adaptive phase 2 neoadjuvant trial ongoing in high-risk clinical stage II/III breast cancer, is designed to evaluate multiple, novel experimental agents added to standard chemotherapy for their ability to improve the rate of pathologic complete response (pCR). Experimental therapies are compared against a common control arm. We report efficacy for the tyrosine kinase inhibitor neratinib. Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR), and MammaPrint. Neratinib was evaluated for 10 signatures (prospectively defined subtype combinations), with primary endpoint pCR. MR volume changes inform likelihood of pCR for each patient prior to surgery. Adaptive assignment to experimental arms within disease subtype was based on current Bayesian probabilities of superiority over control. Accrual to experimental arm stop at any time for futility or graduation within a particular signature based on Bayesian predictive probability of success in a confirmatory trial. The maximum sample size in any experimental arm is 120 patients, Results With 115 patients and 78 concurrently randomized controls, neratinib graduated in the HER2+/HR− signature, with mean pCR rate 56% (95% PI: 37 to 73%) vs 33% for controls (11 to 54%). Final predictive probability of success, updated when all pathology data were available, was 79%. Conclusion Adaptive, multi-armed trials can efficiently identify responding tumor subtypes. Neratinib added to standard therapy is highly likely to improve pCR rates in HER2+/HR2212; breast cancer. Confirmation in I-SPY 3, a phase 3 neoadjuvant registration trial, is planned. PMID:27406346

  2. Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer With Surgery: Is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease?

    SciTech Connect

    Gong Linlin; Wang, Q.I.; Zhao Lujun; Yuan Zhiyong; Li Ruijian; Wang Ping

    2013-01-01

    Purpose: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. Results: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease.

  3. Improving efficiency and reducing costs: Design of an adaptive, seamless, and enriched pragmatic efficacy trial of an online asthma management program.

    PubMed

    Lu, Mei; Ownby, Dennis R; Zoratti, Edward; Roblin, Douglas; Johnson, Dayna; Johnson, Christine Cole; Joseph, Christine L M

    2014-05-01

    Clinical trials are critical for medical decision-making, however, under the current paradigm, clinical trials are fraught with problems including low enrollment and high cost. Promising alternatives to increase trial efficiency and reduce costs include the use of (1) electronic initiatives that permit electronic remote data capture (EDC) for direct data collection at a site (2), electronic medical records (EMR) for patient identification and data collection, and (3) adaptive, enrichment designs with pragmatic approaches. We describe the design of a seamless, multi-site randomized Phase II/III trial to evaluate an asthma management intervention in urban adolescents with asthma. Patients are randomized, asked to access four online sessions of the intervention or control asthma management program, and are then followed for one year. The primary efficacy endpoint is self-reported asthma control as measured by the Asthma Control Test (ACT). Comparative effectiveness parametric approaches are utilized to conduct the trial in a real world setting with reduced costs. Escalated electronic initiatives are implemented for patient identification, assent, enrollment and tracking. Patient enrollment takes place during primary care visits. A centralized database with EDC is used for CRF data collection with integration of EMR data. This Phase II/III trial plans to have a total sample size of 500 patients with an interim look at the completion of Phase II (n=250), The interim analyses include an assessment of the intervention effect, marker(s) identification and the feasibility study of EMR data as the trial CRF data collection. Patient enrollment has begun and is ongoing.

  4. Accelerated dendritic development of rat cortical pyramidal cells and interneurons after biolistic transfection with BDNF and NT4/5.

    PubMed

    Wirth, Marcus J; Brun, Annika; Grabert, Jochen; Patz, Silke; Wahle, Petra

    2003-12-01

    Neurotrophins are candidate molecules for regulating dendritogenesis. We report here on dendritic growth of rat visual cortex pyramidal and interneurons overexpressing 'brain-derived neurotrophic factor' BDNF and 'neurotrophin 4/5' NT4/5. Neurons in organotypic cultures were transfected with plasmids encoding either 'enhanced green fluorescent protein' EGFP, BDNF/EGFP or NT4/5/EGFP either at the day of birth with analysis at 5 days in vitro, or at 5 days in vitro with analysis at 10 days in vitro. In pyramidal neurons, both TrkB ligands increased dendritic length and number of segments without affecting maximum branch order and number of primary dendrites. In the early time window, only infragranular neurons were responsive. Neurons in layers II/III became responsive to NT4/5, but not BDNF, during the later time window. BDNF and NT4/5 transfectants at 10 days in vitro had still significantly shorter dendrites than adult pyramidal neurons, suggesting a massive growth spurt after 10 days in vitro. However, segment numbers were already in the range of adult neurons. Although this suggested a role for BDNF, long-term activity-deprived, and thus BDNF-deprived, pyramidal cells developed a dendritic complexity not different from neurons in active cultures except for higher spine densities on neurons of layers II/III and VI. Neutralization of endogenous NT4/5 causes shorter and less branched dendrites at 10 days in vitro suggesting an essential role for NT4/5. Neutralization of BDNF had no effect. Transfected multipolar interneurons became identifiable during the second time window. Both TrkB ligands significantly increased number of segments and branch order towards the adult state with little effects on dendritic length. The results suggested that early in development BDNF and NT4/5 probably accelerate dendritogenesis in an autocrine fashion. In particular, branch formation was advanced towards the adult pattern in pyramidal cells and interneurons.

  5. Pharmacokinetics of tiotropium administered by Respimat(®) in asthma patients: Analysis of pooled data from Phase II and III clinical trials.

    PubMed

    Sharma, Ashish; Kerstjens, Huib A M; Aalbers, René; Moroni-Zentgraf, Petra; Weber, Benjamin; Dahl, Ronald

    2017-02-01

    Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat(®) inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ss and Cmax,ss. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 μg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 μg once daily or 2.5 μg twice daily via Respimat(®)). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUCtau,ss) was similar between asthma and COPD, but Cmax,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower Cmax,ss compared to COPD is not considered a concern for tiotropium therapy of asthma.

  6. Peptide fragments of the dihydropyridine receptor can modulate cardiac ryanodine receptor channel activity and sarcoplasmic reticulum Ca2+ release.

    PubMed Central

    Dulhunty, Angela F; Curtis, Suzanne M; Cengia, Louise; Sakowska, Magdalena; Casarotto, Marco G

    2004-01-01

    We show that peptide fragments of the dihydropyridine receptor II-III loop alter cardiac RyR (ryanodine receptor) channel activity in a cytoplasmic Ca2+-dependent manner. The peptides were AC (Thr-793-Ala-812 of the cardiac dihydropyridine receptor), AS (Thr-671-Leu-690 of the skeletal dihydropyridine receptor), and a modified AS peptide [AS(D-R18)], with an extended helical structure. The peptides added to the cytoplasmic side of channels in lipid bilayers at > or = 10 nM activated channels when the cytoplasmic [Ca2+] was 100 nM, but either inhibited or did not affect channel activity when the cytoplasmic [Ca2+] was 10 or 100 microM. Both activation and inhibition were independent of bilayer potential. Activation by AS, but not by AC or AS(D-R18), was reduced at peptide concentrations >1 mM in a voltage-dependent manner (at +40 mV). In control experiments, channels were not activated by the scrambled AS sequence (ASS) or skeletal II-III loop peptide (NB). Resting Ca2+ release from cardiac sarcoplasmic reticulum was not altered by peptide AC, but Ca2+-induced Ca2+ release was depressed. Resting and Ca2+-induced Ca2+ release were enhanced by both the native and modified AS peptides. NMR revealed (i) that the structure of peptide AS(D-R18) is not influenced by [Ca2+] and (ii) that peptide AC adopts a helical structure, particularly in the region containing positively charged residues. This is the first report of specific functional interactions between dihydropyridine receptor A region peptides and cardiac RyR ion channels in lipid bilayers. PMID:14678014

  7. A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer's Disease.

    PubMed

    Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

    2016-01-01

    One century after its first description, pathology of Alzheimer's disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD

  8. Trends in Opioid Prescriptions among Part D Medicare Recipients from 2007 to 2012

    PubMed Central

    Kuo, Yong-Fang; Raji, Mukaila A.; Chen, Nai-Wei; Hasan, Hunaid; Goodwin, James S.

    2015-01-01

    Background There is growing concern about potential overuse of, and toxicity from, opioid analgesics. No nationally representative study has examined inter-state variations in opioid use and impact of policy on opioid use among older adults. Methods We used national Medicare data from 2007-2012 to assess temporal and geographic trends in rates of opioid prescription and relationship to opioid toxicity and different state regulations in Part D Medicare recipients. We excluded those with a cancer diagnosis. Multilevel, multivariable regression analyses evaluated rates of prolonged prescriptions for schedule II, schedule III, and combination II/III opioid for each state, adjusting for patient characteristics. Results The percent of Part D recipients receiving prescriptions for combined schedule II/III opioid more than 90 days in a year increased from 4.62% in 2007 to 7.35% in 2012. Large variations existed among states in rates of opioid prescriptions: from 2.84% in New York to 10.93% in Utah, in 2012 data. The state variation was larger for schedule III than schedule II. Individual characteristics independently associated with prolonged use included older age, female gender, white race, low-income, living in a lower education area, and comorbidity of drug abuse, rheumatoid arthritis, depression. Only state law regulating pain clinic was associated with reduction of schedule II opioid prescriptions. Prolonged opioid prescription use increased the odds of opioid overdose-related emergency room visits or hospitalization by 60%. Conclusions Analyses of Medicare Part D data demonstrated a substantial growth in opioid prescriptions from 2007 to 2011 and large variation in opioid prescriptions across states. PMID:26522794

  9. Monoclonal antibodies with selective specificity towards different glycosylation isoforms of FGFR1.

    PubMed

    Gorbenko, Olena; Ovcharenko, Galina; Volkova, Darija; Mayilo, Dmytro; Gaman, Nadia; Khozhayenko, Yulia; Usenko, Valeriy; Gout, Ivan; Filonenko, Valeriy

    2009-08-01

    Fibroblast growth factor receptor 1 (FGFR1) is a member of the FGFR family of receptor tyrosine kinases, whose function has been implicated in diverse biological processes including cell proliferation, differentiation, survival, and tumorigenesis. This diversity is possibly mediated by the existence of multiple FGFR1 isoforms, generated by alternative splicing and post-translational modifications, mainly through glycosylation. In this study we report the generation and characterization of a panel of monoclonal antibodies directed towards FGFR1. To achieve this, we used as an antigen a fragment of FGFR1, corresponding to loop II-III of the extracellular domain, which shares low homology to other members of the FGFR family and possesses numerous antigentic determinants. Two rounds of ELISA screening and Western blot analysis allowed us to isolate a panel of monoclonal antibodies, which recognize specifically recombinant FGFR1 loop II-III. The ability of generated antibodies to recognize endogenous FGFR1 was examined in 3T3 L1 cells, which are known to express FGFR1, but not other members of FGFR family. Immunoblot analysis of 3T3 L1 cell lysates with hybridoma media of selected clones revealed a different, but overlapping pattern of immunoreactive bands, which might represent splicing and post-translationally modified forms of FGFR1. Furthermore, we also tested the cross-reactivity of generated antibodies towards recombinant full-length FGFR3 and their ability to recognize FGFR1 in 3T3 L1 cells by cyto- and immunocytochemistry. In summary, generated antibodies should be useful as tools for examining the expression pattern and biological functions of FGFR1 in normal and pathological tissues.

  10. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    PubMed

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  11. An 8-gene signature for prediction of prognosis and chemoresponse in non-small cell lung cancer

    PubMed Central

    Nguyen, Minh Nam; Matondo, Abel; Jo, Yong Hwa; Yoo, Ji Youn; Nguyen, Ngoc Ngo Yen; Yun, Hyeong Rok; Kim, Jieun; Akter, Salima; Kang, Insug; Ha, Joohun; Maeng, Chi Hoon; Kim, Si-Young; Lee, Ju-seog; Kim, Jayoung; Kim, Sung Soo

    2016-01-01

    Identification of a potential gene signature for improved diagnosis in non-small cell lung cancer (NSCLC) patient is necessary. Here, we aim to establish and validate the prognostic efficacy of a gene set that can predict prognosis and benefits of adjuvant chemotherapy (ACT) in NSCLC patients from various ethnicities. An 8-gene signature was calculated from the gene expression of 181 patients using univariate Cox proportional hazard regression analysis. The prognostic value of the signature was robustly validated in 1,477 patients from five microarray independent data sets and one RNA-seq data set. The 8-gene signature was identified as an independent predictor of patient survival in the presence of clinical parameters in univariate and multivariate analyses [hazard ratio (HR): 2.84, 95% confidence interval CI (1.74-4.65), p=3.06e-05, [HR] 2.62, 95% CI (1.51-4.53), p=0.001], respectively. Subset analysis demonstrated that the 8-gene signature could identify high-risk patients in stage II-III with improved survival from ACT [(HR) 1.47, 95% CI (1.01-2.14), p=0.044]. The 8-gene signature also stratified risk groups in EGFR-mutated and wild-type patients. In conclusion, the 8-gene signature is a strong and independent predictor that can significantly stratify patients into low- and high-risk groups. Our gene signature also has the potential to predict patients in stage II-III that are likely to benefit from ACT. PMID:27863408

  12. Neoadjuvant chemoradiotherapy followed by esophagectomy vs. surgery alone in the treatment of resectable esophageal squamous cell carcinoma

    PubMed Central

    FUJIWARA, YOSHINORI; YOSHIKAWA, REIGETSU; KAMIKONYA, NORIHIKO; NAKAYAMA, TSUYOSHI; KITANI, KOTARO; TSUJIE, MASANORI; YUKAWA, MASAO; HARA, JOHJI; YAMAMURA, TAKEHIRA; INOUE, MASATOSHI

    2013-01-01

    In order to improve the survival of esophageal cancer patients, a trimodality therapy consisting of esophagectomy in combination with neoadjuvant chemoradiotherapy (CRT) has been developed. In this study, we evaluated whether neoadjuvant CRT improved the outcomes of patients with resectable esophageal squamous cell carcinoma (ESCC) compared to surgery alone. Eighty-eight patients with resectable ESCC were treated with either neoadjuvant CRT followed by surgical resection (Group A, n=52), or surgery alone (Group B, n=36). CRT consisted of 5-fluorouracil (5-FU, 500 mg/m2 on days 1–5) and cisplatin (CDDP, 10–20 mg/kg body weight on days 1–5), repeated after 3 weeks. Survival analysis was performed using the log-rank test with the Kaplan-Meier method. The clinical response of the primary tumor and metastatic nodes was 80.8%. The postoperative complications profile was similar between the two groups, except for anastomotic leakage. The median survival time (MST) was not reached in Group A and was 27.4 months in Group B. The estimated 5-year overall survival (OS) rate was 50.3% in Group A and 39.9% in Group B (P=0.134). As regards stage II/III disease, Group A exhibited a better disease-free survival (DFS) compared to Group B (5-year DFS: 57.2% in Group A vs. 31.4% in Group B; P=0.025). Simultaneous locoregional and distant recurrences were more common in the surgery alone group (Group B, P=0.047). Neoadjuvant CRT with 5-FU and CDDP did not contribute to a better prognosis in patients with resectable ESCC. However, it may be beneficial for patients with stage II/III disease. PMID:24649245

  13. Comprehensive Chronic Laminar Single-Unit, Multi-Unit, and Local Field Potential Recording Performance With Planar Single Shank Electrode Arrays

    PubMed Central

    Kozai, Takashi D. Y.; Du, Zhanhong; Gugel, Zhannetta V.; Smith, Matthew A.; Chase, Steven M.; Bodily, Lance M; Caparosa, Ellen M.; Friedlander, Robert M.; Cui, X. Tracy

    2015-01-01

    Background Intracortical electrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. In general, these electrode devices suffer from reliability and variability issues, which have led to comparative studies of existing and emerging electrode designs to optimize performance. Comparisons of different chronic recording devices have been limited to single-unit (SU) activity and employed a bulk averaging approach treating brain architecture as homogeneous with respect to electrode distribution. New Method In this study, we optimize the methods and parameters to quantify evoked multi-unit (MU) and local field potential (LFP) recordings in 8 mice visual cortices. Results These findings quantify the large recording differences stemming from anatomical differences in depth and the layer dependent relative changes to SU and MU recording performance over 6-months. For example, performance metrics in Layer V and stratum pyramidale were initially higher than Layer II/III, but decrease more rapidly. On the other hand, Layer II/III maintained recording metrics longer. In addition, chronic changes at the level of layer IV are evaluated using visually evoked current source density. Comparison with Existing Method(s) The use of MU and LFP activity for evaluation and tracking biological depth provides a more comprehensive characterization of the electrophysiological performance landscape of microelectrodes. Conclusions A more extensive spatial and temporal insight into the chronic electrophysiological performance over time will help uncover the biological and mechanical failure mechanisms of the neural electrodes and direct future research toward the elucidation of design optimization for specific applications. PMID:25542351

  14. Verbal Inflectional Morphology in L1 and L2 Spanish: A Frequency Effects Study Examining Storage versus Composition.

    PubMed

    Bowden, Harriet Wood; Gelfand, Matthew P; Sanz, Cristina; Ullman, Michael T

    2010-02-17

    This study examines the storage vs. composition of Spanish inflected verbal forms in L1 and L2 speakers of Spanish. L2 participants were selected to have mid-to-advanced proficiency, high classroom experience, and low immersion experience, typical of medium-to-advanced foreign language learners. Participants were shown the infinitival forms of verbs from either Class I (the default class, which takes new verbs) or Classes II and III (non-default classes), and were asked to produce either first-person singular present-tense or imperfect forms, in separate tasks. In the present tense, the L1 speakers showed inflected-form frequency effects (i.e., higher frequency forms were produced faster, which is taken as a reflection of storage) for stem-changing (irregular) verb-forms from both Class I (e.g., pensar-pienso) and Classes II and III (e.g., perder-pierdo), as well as for non-stem-changing (regular) forms in Classes II/III (e.g., vender-vendo), in which the regular transformation does not appear to constitute a default. In contrast, Class I regulars (e.g., pescar-pesco), whose non-stem-changing transformation constitutes a default (e.g., it is applied to new verbs), showed no frequency effects. L2 speakers showed frequency effects for all four conditions (Classes I and II/III, regulars and irregulars). In the imperfect tense, the L1 speakers showed frequency effects for Class II/III (-ía-suffixed) but not Class I (-aba-suffixed) forms, even though both involve non-stem-change (regular) default transformations. The L2 speakers showed frequency effects for both types of forms. The pattern of results was not explained by a wide range of potentially confounding experimental and statistical factors, and does not appear to be compatible with single-mechanism models, which argue that all linguistic forms are learned and processed in associative memory. The findings are consistent with a dual-system view in which both verb class and regularity influence the storage vs

  15. Verbal Inflectional Morphology in L1 and L2 Spanish: A Frequency Effects Study Examining Storage versus Composition

    PubMed Central

    Bowden, Harriet Wood; Gelfand, Matthew P.; Sanz, Cristina; Ullman, Michael T.

    2009-01-01

    This study examines the storage vs. composition of Spanish inflected verbal forms in L1 and L2 speakers of Spanish. L2 participants were selected to have mid-to-advanced proficiency, high classroom experience, and low immersion experience, typical of medium-to-advanced foreign language learners. Participants were shown the infinitival forms of verbs from either Class I (the default class, which takes new verbs) or Classes II and III (non-default classes), and were asked to produce either first-person singular present-tense or imperfect forms, in separate tasks. In the present tense, the L1 speakers showed inflected-form frequency effects (i.e., higher frequency forms were produced faster, which is taken as a reflection of storage) for stem-changing (irregular) verb-forms from both Class I (e.g., pensar-pienso) and Classes II and III (e.g., perder-pierdo), as well as for non-stem-changing (regular) forms in Classes II/III (e.g., vender-vendo), in which the regular transformation does not appear to constitute a default. In contrast, Class I regulars (e.g., pescar-pesco), whose non-stem-changing transformation constitutes a default (e.g., it is applied to new verbs), showed no frequency effects. L2 speakers showed frequency effects for all four conditions (Classes I and II/III, regulars and irregulars). In the imperfect tense, the L1 speakers showed frequency effects for Class II/III (-ía-suffixed) but not Class I (-aba-suffixed) forms, even though both involve non-stem-change (regular) default transformations. The L2 speakers showed frequency effects for both types of forms. The pattern of results was not explained by a wide range of potentially confounding experimental and statistical factors, and does not appear to be compatible with single-mechanism models, which argue that all linguistic forms are learned and processed in associative memory. The findings are consistent with a dual-system view in which both verb class and regularity influence the storage vs

  16. Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat

    PubMed Central

    Wang, Yun; Toledo-Rodriguez, Maria; Gupta, Anirudh; Wu, Caizhi; Silberberg, Gilad; Luo, Junyi; Markram, Henry

    2004-01-01

    Whole-cell patch-clamp recordings followed by histochemical staining and single-cell RT-PCR were obtained from 180 Martinotti interneurones located in layers II to VI of the somatosensory cortex of Wistar rats (P13–P16) in order to examine their anatomical, electrophysiological and molecular properties. Martinotti cells (MCs) mostly displayed ovoid-shaped somata, bitufted dendritic morphologies, and axons with characteristic spiny boutons projecting to layer I and spreading horizontally across neighbouring columns more than 1 mm. Electron microscopic examination of MC boutons revealed that all synapses were symmetrical and most synapses (71%) were formed onto dendritic shafts. MCs were found to contact tuft, apical and basal dendrites in multiple neocortical layers: layer II/III MCs targeted mostly layer I and to a lesser degree layer II/III; layer IV MCs targeted mostly layer IV and to a lesser degree layer I; layer V and VI MCs targeted mostly layer IV and layer I and to a lesser degree the layer in which their somata was located. MCs typically displayed spike train accommodation (90%; n = 127) in response to depolarizing somatic current injections, but some displayed non-accommodating (8%) and a few displayed irregular spiking responses (2%). Some accommodating and irregular spiking MCs also responded initially with bursts (17%). Accommodating responses were found in all layers, non-accommodating mostly in upper layers and bursting mostly in layer V. Single-cell multiplex RT-PCR performed on 63 MCs located throughout layers II–VI, revealed that all MCs were somatostatin (SOM) positive, and negative for parvalbumin (PV) as well as vasoactive intestinal peptide (VIP). Calbindin (CB), calretinin (CR), neuropeptide Y (NPY) and cholecystokinin (CCK) were co- expressed with SOM in some MCs. Some layer-specific trends seem to exist. Finally, 24 accommodating MCs were examined for the expression of 26 ion channel genes. The ion channels with the highest expression

  17. Molecular identification of an N-type Ca2+ channel in saccular hair cells.

    PubMed

    Ramakrishnan, N A; Drescher, M J; Sheikhali, S A; Khan, K M; Hatfield, J S; Dickson, M J; Drescher, D G

    2006-01-01

    We report new molecular evidence for the presence of an N-type (Ca(v)2.2, alpha1B) voltage-gated Ca(2+) channel in hair cells of the saccular epithelium of the rainbow trout. The Ca(v)2.2 amino-acid sequence shows 68% and 63% identity compared with chick and human Ca(v)2.2, respectively. This channel reveals features that are characteristic of an N-type Ca(2+) channel: an omega-conotoxin GVIA binding domain, G(betagamma) binding regions, and a synaptic protein interaction site. Immunohistochemical studies with a custom antibody show that immunoreactivity for the Ca(v)2.2 is concentrated in the basolateral and apical regions of hair cells. Whereas trout brain and saccular macula express an 11-amino-acid insert in the second G(betagamma) binding domain of the Ca(v)2.2 I-II loop, isolated hair cells appear not to express this variant. We constructed fusion polypeptides representing portions of the I-II loop, beta1 and beta2a auxiliary subunits, the II-III loop, and syntaxin, and examined their intermolecular interactions via immunoprecipitation and surface plasmon resonance. The I-II loop polypeptides bound both beta1 and beta2a subunits with a preference for beta1, and the II-III loop exhibited Ca(2+)-dependent syntaxin binding. We demonstrated syntaxin immunoreactivity near afferent endings in hair cells, at hair-cell apices, and in efferent endings on hair cells, the former two sites consistent with binding of syntaxin to Ca(v)2.2. The present molecular characterization of the Ca(v)2.2 channel provides novel biochemical evidence for an N-type channel in hair cells, and details molecular interactions of this channel that reflect hair-cell function, such as spontaneous activity and vesicular trafficking. The current work, to our knowledge, represents the first demonstration of a putative N-type channel in hair cells as documented by tissue-specific antibody immunoreactivity and hair-cell-specific cDNA sequence.

  18. TERT PROMOTER MUTATIONS OCCUR FREQUENTLY IN GLIOMAS AND A SUBSET OF TUMORS DERIVED FROM CELLS WITH LOW RATES OF SELF-RENEWAL

    PubMed Central

    Yan, Hai; Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; Grollman, A.P.; He, T.C.; He, Y.; Hruban, R.H.; Jallo, G.I.; Mandahl, N.; Meeker, A.K.; Mertens, F.; Netto, G.J.; Rasheed, B.A.; Riggins, G.J.; Rosenquist, T.A.; Schiffman, M.; Shih, IeM; Theodorescu, D.; Torbenson, M.S.; Velculescu, V.E.; Wang, T.L.; Wentzensen, N.; Wood, L.D.; Zhang, M.; Healy, P.; Yang, R.; Diplas, B.; Wang, Z.H.; Greer, P.; Zhu, H.S.; Wang, C.; Carpenter, A.; Herndon, J.E.; McLendon, R.E.; Kinzler, K.W.; Vogelstein, B.; Papadopoulos, N.; Bigner, D.D.

    2014-01-01

    BACKGROUND: Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas. METHODS: To further define the tumor types in which TERT plays a role, we surveyed 1,230 tumors of 60 different types. We also analyzed the relationship between median overall survival (OS) of patients with IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas with the hypothesis that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. RESULTS: We found that tumors could be divided into types with low and high frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas. TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of

  19. Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success.

    PubMed

    Pogue, Brian W; Elliott, Jonathan T; Kanick, Stephen C; Davis, Scott C; Samkoe, Kimberley S; Maytin, Edward V; Pereira, Stephen P; Hasan, Tayyaba

    2016-04-07

    Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment

  20. The acute effect of bipolar radiofrequency energy thermal chondroplasty on intrinsic biomechanical properties and thickness of chondromalacic human articular cartilage.

    PubMed

    Dutcheshen, Nicholas; Maerz, Tristan; Rabban, Patrick; Haut, Roger C; Button, Keith D; Baker, Kevin C; Guettler, Joseph

    2012-08-01

    Radio frequency energy (RFE) thermal chondroplasty has been a widely-utilized method of cartilage debridement in the past. Little is known regarding its effect on tissue mechanics. This study investigated the acute biomechanical effects of bipolar RFE treatment on human chondromalacic cartilage. Articular cartilage specimens were extracted (n = 50) from femoral condyle samples of patients undergoing total knee arthroplasty. Chondromalacia was graded with the Outerbridge classification system. Tissue thicknesses were measured using a needle punch test. Specimens underwent pretreatment load-relaxation testing using a spherical indenter. Bipolar RFE treatment was applied for 45 s and the indentation protocol was repeated. Structural properties were derived from the force-time data. Mechanical properties were derived using a fibril-reinforced biphasic cartilage model. Statistics were performed using repeated measures ANOVA. Cartilage thickness decreased after RFE treatment from a mean of 2.61 mm to 2.20 mm in Grade II, II-III, and III specimens (P < 0.001 each). Peak force increased after RFE treatment from a mean of 3.91 N to 4.91 N in Grade II and III specimens (P = 0.002 and P = 0.003, respectively). Equilibrium force increased after RFE treatment from a mean of 0.236 N to 0.457 N (P < 0.001 each grade). Time constant decreased after RFE treatment from a mean of 0.392 to 0.234 (P < 0.001 for each grade). Matrix modulus increased in all specimens following RFE treatment from a mean 259.12 kPa to 523.36 kPa (P < 0.001 each grade). Collagen fibril modulus decreased in Grade II and II-III specimens from 60.50 MPa to 42.04 MPa (P < 0.001 and P = 0.005, respectively). Tissue permeability decreased in Grade II and III specimens from 2.04 ∗10(-15) m(4)/Ns to 0.91 ∗10(-15) m(4)/Ns (P < 0.001 and P = 0.009, respectively). RFE treatment decreased thickness, time constant, fibril modulus, permeability, but increased peak force

  1. Re-Os Geochronology Pins Age and Os Isotope Composition of Middle Triassic Black Shales and Seawater, Barents Sea and Spitsbergen (Svalbard)

    NASA Astrophysics Data System (ADS)

    Xu, G.; Hannah, J. L.; Bingen, B.; Stein, H. J.; Yang, G.; Zimmerman, A.; Weitschat, W.; Weiss, H. M.

    2008-12-01

    Absolute age control throughout the Triassic is extraordinarily sparse. Two "golden spikes" have been added recently (http://www.stratigraphy.org/cheu.pdf) within the otherwise unconstrained Triassic, but ages of stage boundaries remain controversial. Here we report two Re-Os isochrons for Anisian (Middle Triassic) black shales from outcrop in western Svalbard and drill core from the Svalis Dome about 600 km to the SE in the Barents Sea. Black shales of the Blanknuten Member, Botneheia Formation, from the type section at Botneheia, western Spitsbergen (Svalbard), have total organic carbon (TOC) contents of 2.6 to 6.0 wt%. Rock-Eval data suggest moderately mature (Tmax = 440-450° C) Type II-III kerogens (Hydrogen Index (HI) = 232-311 mg HC/g TOC). Re-Os data yield a well-constrained Model 3 age of 241 Ma and initial 187Os/188Os (Osi) of 0.83 (MSWD = 16, n = 6). Samples of the possibly correlative Steinkobbe Formation from IKU core hole 7323/07-U-04 into the Svalis Dome in the Barents Sea (at about 73°30'N, 23°15'E) have TOC contents of 1.4 to 2.4%. Rock-Eval data suggest immature (Tmax = 410-430°) Type II-III kerogens (HI = 246-294 mg HC/g TOC). Re-Os data yield a precise Model 1 age of 239 Ma and Osi of 0.776 (MSWD = 0.2, n = 5). The sampled section of Blanknuten shale underlies a distinctive Frechitas (formerly Ptychites) layer, and is therefore assumed to be middle Anisian. The Steinkobbe core was sampled at 99-100 m, just above the Olenekian-Anisian transition. It is therefore assumed to be lower Anisian. The two isochron ages overlap within uncertainty, and fall within constraints provided by biozones and the current ICS-approved stage boundary ages. The Re-Os ages support the correlation of the Botneheia and Steinkobbe formations. The nearly identical Osi ratios suggest regional homogeneity of seawater and provide new information for the Os seawater curve, marking a relatively high 187Os/188Os ratio during profound ocean anoxia in the Middle Triassic.

  2. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    SciTech Connect

    Paez, David; Salazar, Juliana; Pare, Laia; Pertriz, Lourdes; Targarona, Eduardo; Rio, Elisabeth del; Barnadas, Agusti; Marcuello, Eugenio; Baiget, Montserrat

    2011-12-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5 Prime UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The Asterisk-Operator 3/ Asterisk-Operator 3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in Asterisk-Operator 3/ Asterisk-Operator 3 vs. 35% in Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk-Operator 3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the Asterisk-Operator 3/ Asterisk-Operator 3 patients and 84 months for the Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk

  3. Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

    NASA Astrophysics Data System (ADS)

    Pogue, Brian W.; Elliott, Jonathan T.; Kanick, Stephen C.; Davis, Scott C.; Samkoe, Kimberley S.; Maytin, Edward V.; Pereira, Stephen P.; Hasan, Tayyaba

    2016-04-01

    Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment

  4. The oral administration of D-galactose induces abnormalities within the mitochondrial respiratory chain in the brain of rats.

    PubMed

    Budni, Josiane; Garcez, Michelle Lima; Mina, Francielle; Bellettini-Santos, Tatiani; da Silva, Sabrina; Luz, Aline Pereira da; Schiavo, Gustavo Luiz; Batista-Silva, Hemily; Scaini, Giselli; Streck, Emílio Luiz; Quevedo, João

    2017-02-24

    D-Galactose (D-gal) chronic administration via intraperitoneal and subcutaneous routes has been used as a model of aging and Alzheimer disease in rodents. Intraperitoneal and subcutaneous administration of D-gal causes memory impairments, a reduction in the neurogenesis of adult mice, an increase in the levels of the amyloid precursor protein and oxidative damage; However, the effects of oral D-gal remain unclear. The aim of this study was to evaluate whether the oral administration of D-gal induces abnormalities within the mitochondrial respiratory chain of rats. Male Wistar rats (4 months old) received D-gal (100 mg/kg v.o.), during the 1st, 2nd, 4th, 6th or 8th weeks by oral gavage. The activity of the mitochondrial respiratory chain complexes was measured in the 1st, 2nd, 4th, 6th and 8th weeks after the administration of D-gal. The activity of the respiratory chain complex I was found to have increased in the prefrontal cortex and hippocampus in the 1st, 6th and 8th weeks, while the activity of the respiratory chain complex II increased in the 1st, 2nd, 4th, 6th and 8th weeks within the hippocampus and in the 2nd, 4th, 6th and 8th weeks within the prefrontal cortex. The activity of complex II-III increased within the prefrontal cortex and hippocampus in each week of oral D-gal treatment. The activity of complex IV increased within the prefrontal cortex and hippocampus in the 1st, 2nd, 6th and 8th weeks of treatment. After 4 weeks of treatment the activity increased only in hippocampus. In conclusion, the present study showed that the oral administration of D-gal increased the activity of the mitochondrial respiratory chain complexes I, II, II-III and IV in the prefrontal cortex and hippocampus. Furthermore, the administration of D-gal via the oral route seems to cause the alterations in the mitochondrial respiratory complexes observed in brain neurodegeneration.

  5. The master T-operator for the Gaudin model and the KP hierarchy

    NASA Astrophysics Data System (ADS)

    Alexandrov, Alexander; Leurent, Sebastien; Tsuboi, Zengo; Zabrodin, Anton

    2014-06-01

    Following the approach of [1], we construct the master T-operator for the quantum Gaudin model with twisted boundary conditions and show that it satisfies the bilinear identity and Hirota equations for the classical KP hierarchy. We also characterize the class of solutions to the KP hierarchy that correspond to eigenvalues of the master T-operator and study dynamics of their zeros as functions of the spectral parameter. This implies a remarkable connection between the quantum Gaudin model and the classical Calogero-Moser system of particles. The quantum Gaudin model, The classical Kadomtsev-Petviashvili (KP) hierarchy, The classical Calogero-Moser (CM) system of particles. The link (i)-(ii) is a limiting case of the correspondence between quantum spin chains with the Yangian Y(gl(N))-invariant rational R-matrices and the classical modified KP hierarchy based on the construction of the master T-operator [1,2]. The link (ii)-(iii) is a well-known story about dynamics of poles of rational solutions to soliton equations started by Airault, McKean and Moser [3] for the KdV equation, developed by Krichever [4] for the KP equation and extended to the whole KP hierarchy by Shiota [5]. The composition of (i)-(ii) and (ii)-(iii) implies the connection between the quantum Gaudin model and the classical CM model which is a limiting case of the connection between quantum spin chains and classical Ruijsenaars systems found in [1]. The link (i)-(iii) was also earlier established in [6] from a different reasoning.The master T-operator was introduced in [1]. We construct commuting integrals of motion for the gl(N) Gaudin model, with twisted boundary conditions and vector representations at the marked points in the quantum space, corresponding to arbitrary representations in the auxiliary space. They are presented in an explicit form using the matrix derivative operation. We also find functional relations satisfied by them. The master T-operator for the gl(N) Gaudin model is the

  6. Two-Center/Three-Electron Sigma Half-Bonds in Main Group and Transition Metal Chemistry.

    PubMed

    Berry, John F

    2016-01-19

    First proposed in a classic Linus Pauling paper, the two-center/three-electron (2c/3e) σ half-bond challenges the extremes of what may or may not be considered a chemical bond. Two electrons occupying a σ bonding orbital and one electron occupying the antibonding σ* orbital results in bond orders of ∼0.5 that are characteristic of metastable and exotic species, epitomized in the fleetingly stable He2(+) ion. In this Account, I describe the use of coordination chemistry to stabilize such fugacious three-electron bonded species at disparate ends of the periodic table. A recent emphasis in the chemistry of metal-metal bonds has been to prepare compounds with extremely short metal-metal distances and high metal-metal bond orders. But similar chemistry can be used to explore metal-metal bond orders less than one, including 2c/3e half-bonds. Bimetallic compounds in the Ni2(II,III) and Pd2(II,III) oxidation states were originally examined in the 1980s, but the evidence collected at that time suggested that they did not contain 2c/3e σ bonds. Both classes of compounds have been re-examined using EPR spectroscopy and modern computational methods that show the unpaired electron of each compound to occupy a M-M σ* orbital, consistent with 2c/3e Ni-Ni and Pd-Pd σ half-bonds. Elsewhere on the periodic table, a seemingly unrelated compound containing a trigonal bipyramidal Cu3S2 core caused a stir, leaving prominent theorists at odds with one another as to whether the compound contains a S-S bond. Due to my previous experience with 2c/3e metal-metal bonds, I suggested that the Cu3S2 compound could contain a 2c/3e S-S σ half-bond in the previously unknown oxidation state of S2(3-). By use of the Cambridge Database, a number of other known compounds were identified as potentially containing S2(3-) ligands, including a noteworthy set of cyclopentadienyl-supported compounds possessing diamond-shaped Ni2E2 units with E = S, Se, and Te. These compounds were subjected to

  7. Knowledge creation about ADRs – turning the perspective from the rear mirror to the projector?

    PubMed Central

    Aagaard, Lise; Soendergaard, Birthe; Stenver, Doris I; Hansen, Ebba Holme

    2008-01-01

    Aims Spontaneous reports of adverse drug reactions (ADRs) are often the only documentation used to justify the recall of drugs from the market. The purpose of this study was to investigate whether it would have been possible to foresee serious ADR cases based on available information on ADRs reported in Phase II and III clinical trials before marketing. Methods We conducted a retrospective analysis of reported ADR data in Phase II/III clinical trials in the registration material for three different ADR scenarios: (i) trovafloxacin/alatrofloxacin and hepatotoxicity; (ii) tolcapone and hepatotoxicity and neuroleptic malignant syndrome; and (iii) rituximab and cytokine release syndrome. We chose the scenarios because they were of serious character and caused great damage to the patients and because of different outcomes of the scientific discussions in the regulatory agencies. Results In all three cases, the registration material contained observations of ADRs, but there had been no follow-up on these observations. ADRs were mentioned in the summary of product information (SPC) purely as information, to some extent accompanied by recommendations. The information was not converted into new knowledge and remained tacit knowledge embedded in the SPCs disseminated to health professionals/prescribers. Conclusions The registration material analysed contained information about ADRs that were reported later, meaning that it would have been possible to foresee the occurrence of the ADRs at the time of licensing. More active utilization of the information from Phase II/III clinical trials is recommended to prevent the appearance of unexpected ADRs and further emphasis in SPC warnings to doctors about possible serious ADRs. What is already known about this subject? Serious and unexpected adverse drug reactions (ADRs) have been reported shortly after marketing of a number of drugs.Review of ADR cases by the regulatory authorities has resulted in suspension of drugs or

  8. Adjuvant chemotherapy, p53, carcinoembryonic antigen expression and prognosis after D2 gastrectomy for gastric adenocarcinoma

    PubMed Central

    He, Ming-Ming; Zhang, Dong-Sheng; Wang, Feng; Wang, Zhi-Qiang; Luo, Hui-Yan; Ren, Chao; Jin, Ying; Chen, Dong-Liang; Xu, Rui-Hua

    2014-01-01

    AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma. METHODS: A total of 286 patients with stage II or III gastric adenocarcinoma who underwent D2 radical gastrectomy between May 2007 and December 2010 were enrolled into this study. One hundred and sixty-nine of these patients received surgery plus adjuvant chemotherapy, and 117 patients received surgery alone. Tumor expression of p53 and CEA proteins in all patients was evaluated immunohistochemically and correlated with clinicopathological parameters. The Kaplan-Meier curves for overall survival (OS) and disease-free survival (DFS) with log-rank testing were used to compare the survival difference. A Cox proportional hazard regression model was used for multivariate analysis. RESULTS: Patients with adjuvant chemotherapy had a significantly better median OS (50.87 mo vs 30.73 mo, P = 0.000) and median DFS (36.30 mo vs 25.60 mo, P = 0.001) than patients with surgery alone in the entire cohort. Consistent results with the entire cohort were found in stage II (P = 0.006 and P = 0.047), stage III (P = 0.005 and P = 0.030), and stage IIIB/IIIC patients (P = 0.000 and P = 0.001). The median OS and DFS advantages were confirmed by multivariate analysis (P = 0.000 and P = 0.008) and maintained when the analyses were restricted to fluoropyrimidine monotherapy (P = 0.003 and P = 0.001) and fluoropyrimidine plus platinum regimen (P = 0.001 and P = 0.007), however, not the fluoropyrimidine plus taxane (P = 0.198 and P = 0.777) or platinum plus taxane (P = 0.666 and P = 0.687) regimens. Median OS and median DFS did not differ significantly between the patients with p53(+) and p53(-) tumors (P = 0.608 and P = 0.064), or between patients with CEA(+) and CEA(-) tumors (P = 0.052 and P = 0.989), which were maintained when the analyses were restricted to surgery alone (p53: P = 0.864 and P = 0.431; CEA: P = 0.142 and

  9. A Forward Genetic Screen in Mice Identifies Mutants with Abnormal Cortical Patterning

    PubMed Central

    Ha, Seungshin; Stottmann, Rolf W.; Furley, Andrew J.; Beier, David R.

    2015-01-01

    Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain. PMID:23968836

  10. Methicillin-resistant Staphylococcus pseudintermedius among dogs admitted to a small animal hospital.

    PubMed

    Nienhoff, Ulrike; Kadlec, Kristina; Chaberny, Iris F; Verspohl, Jutta; Gerlach, Gerald-F; Kreienbrock, Lothar; Schwarz, Stefan; Simon, Daniela; Nolte, Ingo

    2011-05-12

    The aim of this study was to determine the frequency of carriage of methicillin-resistant Staphylococcus pseudintermedius (MRSP) among dogs admitted to a small animal hospital during a 17-month period, to characterize these isolates and to initially screen for possible factors associated with MRSP carriage. Swabs were taken from the nose/pharynx and the perineum as well as from wounds and skin infections (if present) of 814 dogs before entering the small animal hospital. A questionnaire for background information was completed. The staphylococcal species and methicillin resistance were confirmed pheno- and genotypically. The identified MRSP isolates were characterized by SCCmec typing, testing for susceptibility to 25 antimicrobial agents and SmaI-directed pulsed-field gel electrophoresis. A first screening for possible risk factors for MRSP carriage was performed by means of unifactorial contingency tables and CART analysis. Sixty (7.4%) dogs were positive for MRSP. All MRSP isolates harboured a type II-III SCCmec cassette and showed extended resistance to antimicrobial agents. Fifteen different SmaI patterns were observed. The major factors that clustered with MRSP carriage were former hospitalization and antibiotic treatment within the last six months before sampling. This study showed that only a minor part of the sampled dogs carried multi-resistant MRSP isolates. The facts that prior hospitalization and/or antibiotic therapy are potential associated factors for MRSP carriage underline the necessity of a judicious use of antibiotics in small animal medicine.

  11. Methicillin-resistant Staphylococcus pseudintermedius in Sweden.

    PubMed

    Börjesson, Stefan; Landén, Annica; Bergström, Martin; Andersson, Ulrika Grönlund

    2012-12-01

    Staphylococcus pseudintermedius is an opportunistic pathogen that is one of the most frequent causes of infections in dogs. In Europe, there are increasing reports of methicillin-resistant S. pseudintermedius (MRSP), and in Sweden, MRSP has also been more frequently isolated during recent years. However, there is limited knowledge regarding the epidemiology and genetic relationship among the Swedish isolates. This study therefore investigated the genetic relationship of MRSP isolated from companion animals in Sweden. In the study, MRSP isolates taken in the period January 2008-June 2010 from a total of 226 dogs and cats were characterized by spa typing, pulsed-field gel electrophoresis, and antimicrobial susceptibility testing. In addition, the geographical distribution of the isolates based on year of isolation and genetic typing was determined using a geographical information system. One multiresistant clonal lineage dominated among Swedish MRSP isolates, corresponding to the European winning lineage ST71-J-t02-SCCmec II-III. Furthermore, the geographical dissemination of MRSP corresponded to areas with high dog densities, centered on the three major cities in Sweden where the largest animal hospitals are situated.

  12. Iontophoresis with gold nanoparticles improves mitochondrial activity and oxidative stress markers of burn wounds.

    PubMed

    Silveira, Paulo C L; Venâncio, Mirelli; Souza, Priscila S; Victor, Eduardo G; de Souza Notoya, Frederico; Paganini, Carla S; Streck, Emilio L; da Silva, Luciano; Pinho, Ricardo A; Paula, Marcos M S

    2014-11-01

    The aim of this study was to analyse the effects of microcurrent and gold nanoparticles on oxidative stress parameters and the mitochondrial respiratory chain in the healing of skin wounds. Thirty 60-day old male Wistar rats (250-300 g) were divided into five groups (N=6): Control; Burn wounds; Microcurrent (MIC); Gold nanoparticle gel (GNP gel) and Microcurrent+Gold nanoparticle gel (MIC+GNP gel). The microcurrent treatment was applied for five consecutive days at a dose of 300 μA. The results demonstrate a significant decrease in the activity of complexes I, II-III and IV in the Burn Wounds group compared to the control, and the MIC+GNP gel group was able to reverse this inhibition in complexes I, III and IV. Furthermore, a significant reduction in oxidative damage parameters and a significant increase in the levels of antioxidant defence enzymes were induced in the MIC+GNP gel group compared to the Burn Wounds group. The data strongly indicate that the group receiving treatment with MIC+GNP gel had improved mitochondrial functioning and oxidative stress parameters, which contributed to tissue repair.

  13. Evidence of internucleosomal DNA fragmentation and identification of dying cells in X-ray-induced cell death in the developing brain.

    PubMed

    Ferrer, I; Macaya, A; Blanco, R; Olivé, M; Cinós, C; Munell, F; Planas, A M

    1995-02-01

    Newborn Sprague-Dawley rats received a single dose of 2 Gy X-rays and were killed 6 hr later. Dying cells were characterized by extreme chromatin condensation and nuclear fragmentation. Dying cells were distributed in the primary and secondary germinal zones and in other brain regions. Among these latter, dying cells occurred in the cortical layers of the olfactory bulb, layers II-III and VIb of the neocortex, piriform and entorhinal cortex, stratum oriens and pyramidale of the hippocampus, striatum, thalamus, amygdala, brainstem, internal granular layer of the cerebellum, and cerebral and cerebellar white matter. Dying cells were immature cells, neurons and glial cells (including radial glia). In-situ labeling of nuclear DNA fragmentation identified individual cells bearing fragmented DNA. Since the number of cells stained with this method was larger than the number of dying cells, as revealed with current histological techniques, it is suggested that nuclear DNA fragmentation precedes chromatin condensation and nuclear fragmentation in X-ray-induced apoptosis. Furthermore, agarose gel electrophoresis of extracted DNA from irradiated brains showed a "ladder" pattern which is typical of internucleosomal DNA fragmentation and endonuclease activation.

  14. Management of neuroblastoma: a study of first- and second-line chemotherapy responses, a single institution experience

    PubMed Central

    Habib, Emmad E.; El-Kashef, Amr T.; Fahmy, Ezzat S.

    2012-01-01

    Neuroblastoma is a high-grade malignancy of childhood. It is chemo- and radio-sensitive but prone to relapse after initial remission. The aim of the current study was to study the results of the first- and second-line chemotherapy on the short-term response and long-term survival of children, and to further describe the side effects of treatment. Ninety-five children with advanced neuroblastoma were included in the study, divided into two groups according to the treatment strategy: 65 were treated by first-line chemotherapy alone, and 30 children who were not responding or relapsed after first-line chemotherapy were treated by second-line chemotherapy. External beam radiotherapy was given to bone and brain secondary cancers when detected. Staging workup was performed before, during and after management. Response was documented after surgery for the primary tumor. Median follow up was 32 months (range 24–60 months). Chemothe rapy was continued until toxicity or disease progression occurred, indicating interruption of chemotherapy. Patients received a maximum of 8 cycles. Toxicity was mainly myelo-suppression, with grade II-III severity in 60% of the firstline and 70% of the second-line chemotherapy patients. Median total actuarial survival was nearly 51 months for the first-line chemotherapy group and 30 months for the second-line line group, with a statistically significant difference between the two groups (P<0.01). PMID:25992205

  15. Multimodality treatment of malignant pleural mesothelioma with or without immunotherapy: does it change anything?

    PubMed

    Lucchi, Marco; Picchi, Alessandro; Alí, Greta; Chella, Antonio; Guglielmi, Giovanni; Cristaudo, Alfonso; Fontanini, Gabriella; Mussi, Alfredo

    2010-04-01

    The purpose of this study was to investigate immunological effector cells and angiogenesis in malignant pleural mesothelioma (MPM) patients, who underwent multimodality treatments. Clinical and pathological characteristics of 57 patients, with International Mesothelioma Interest Group stage II-III MPM, who underwent two different multimodality treatments (with and without immunotherapy) between 1999 and 2008 were analyzed. CD8+, CD4+ and Foxp3+ tumor-infiltrating lymphocytes, tryptase and chymase mast cells (MCs), CD34, number of microvessels and vascular endothelial growth factor were determined by immunohistochemistry. The histology was 51 epitheliomorf and 6 biphasic. The stage was III in 41 cases and II in 16 cases. With an average follow-up of 69 months (range 9-115) 14 patients are still alive and the overall median actuarial survival is 21.4 months. Tryptase MCs, CD8+ and Foxp3+ lymphocytes had significantly increased in the interleukin 2 (IL-2) treated group. Moreover, the number of microvessels was significantly lower in IL-2 treated patients. This study indicates that immunotherapy leads to an increase in cytotoxic CD8+ lymphocytes and tryptase MCs and to a decrease of the tumoral neoangiogenesis. Changes in MPM microenvironment induced by immunotherapy may play a major role in the local control of this disease and need further investigations.

  16. Identified Cellular Correlates of Neocortical Ripple and High-Gamma Oscillations during Spindles of Natural Sleep.

    PubMed

    Averkin, Robert G; Szemenyei, Viktor; Bordé, Sándor; Tamás, Gábor

    2016-11-23

    Ultra-high-frequency network events in the hippocampus are instrumental in a dialogue with the neocortex during memory formation, but the existence of transient ∼200 Hz network events in the neocortex is not clear. Our recordings from neocortical layer II/III of freely behaving rats revealed field potential events at ripple and high-gamma frequencies repeatedly occurring at troughs of spindle oscillations during sleep. Juxtacellular recordings identified subpopulations of fast-spiking, parvalbumin-containing basket cells with epochs of firing at ripple (∼200 Hz) and high-gamma (∼120 Hz) frequencies detected during spindles and centered with millisecond precision at the trough of spindle waves in phase with field potential events but phase shifted relative to pyramidal cell firing. The results suggest that basket cell subpopulations are involved in spindle-nested, high-frequency network events that hypothetically provide repeatedly occurring neocortical temporal reference states potentially involved in mnemonic processes.

  17. Coronal Structures in Cool Stars: XMM-NEWTON Hybrid Stars and Coronal Evolution

    NASA Technical Reports Server (NTRS)

    Dupree, Andrea K.; Mushotzky, Richard (Technical Monitor)

    2003-01-01

    This program addresses the evolution of stellar coronas by comparing a solar-like corona in the supergiant Beta Dra (G2 Ib-IIa) to the corona in the allegedly more evolved state of a hybrid star, alpha TrA (K2 II-III). Because the hybrid star has a massive wind, it appears likely that the corona will be cooler and less dense as the magnetic loop structures are no longer closed. By analogy with solar coronal holes, when the topology of the magnetic field is configured with open magnetic structures, both the coronal temperature and density are lower than in atmospheres dominated by closed loops. The hybrid stars assume a pivotal role in the definition of coronal evolution, atmospheric heating processes and mechanisms to drive winds of cool stars. We are attempting to determine if this model of coronal evolution is correct by using XMM-NEWTON RGS spectra for the 2 targets we were allocated through the Guest Observer program.

  18. Late Corrective Arthrodesis in Nonplantigrade Diabetic Charcot Midfoot Disease Is Associated with High Complication and Reoperation Rates

    PubMed Central

    Wussow, Annekatrin

    2015-01-01

    Introduction. Charcot arthropathy may lead to a loss of osteoligamentous foot architecture and consequently loss of the plantigrade alignment. In this series of patients a technique of internal corrective arthrodesis with maximum fixation strength was provided in order to lower complication rates. Materials/Methods. 21 feet with severe nonplantigrade diabetic Charcot deformity Eichenholtz stages II/III (Sanders/Frykberg II/III/IV) and reconstructive arthrodesis with medial and additional lateral column support were retrospectively enrolled. Follow-up averaged 4.0 years and included a clinical (AOFAS score/PSS), radiological, and complication analysis. Results. A mean of 2.4 complications/foot occurred, of which 1.5/foot had to be solved surgically. 76% of feet suffered from soft tissue complications; 43% suffered hardware-associated complications. Feet with only 2 out of 5 high risk criteria according to Pinzur showed significantly lower complication counts. Radiographs revealed a correct restoration of all foot axes postoperatively with superior fixation strength medially. Conclusion. Late corrective arthrodesis with medial and lateral column stabilization in the nonplantigrade stages of neuroosteoarthropathy can provide reasonable reconstruction of the foot alignment. Nonetheless, overall complication/reoperation rates were high. With separation into low/high risk criteria a helpful guide in treatment choice is provided. This trial is registered with German Clinical Trials Register (DRKS) under number DRKS00007537. PMID:26000309

  19. Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizurelike activity in mouse medial entorhinal cortex.

    PubMed

    Yekhlef, Latefa; Breschi, Gian Luca; Lagostena, Laura; Russo, Giovanni; Taverna, Stefano

    2015-03-01

    GABAergic interneurons are thought to play a critical role in eliciting interictal spikes (IICs) and triggering ictal discharges in temporal lobe epilepsy, yet the contribution of different interneuronal subtypes to seizure initiation is still largely unknown. Here we took advantage of optogenetic techniques combined with patch-clamp and field recordings to selectively stimulate parvalbumin (PV)- or somatostatin (SOM)-positive interneurons expressing channelrhodopsin-2 (CHR-2) in layers II-III of adult mouse medial entorhinal cortical slices during extracellular perfusion with the proconvulsive compound 4-aminopyridine (4-AP, 100-200 μM). In control conditions, blue laser photostimulation selectively activated action potential firing in either PV or SOM interneurons and, in both cases, caused a robust GABAA-receptor-mediated inhibition in pyramidal cells (PCs). During perfusion with 4-AP, brief photostimuli (300 ms) activating either PV or SOM interneurons induced patterns of epileptiform activity that closely replicated spontaneously occurring IICs and tonic-clonic ictal discharges. Laser-induced synchronous firing in both interneuronal types elicited large compound GABAergic inhibitory postsynaptic currents (IPSCs) correlating with IICs and preictal spikes. In addition, spontaneous and laser-induced epileptic events were similarly initiated in concurrence with a large increase in extracellular potassium concentration. Finally, interneuron activation was unable to stop or significantly shorten the progression of seizurelike episodes. These results suggest that entorhinal PV and SOM interneurons are nearly equally effective in triggering interictal and ictal discharges that closely resemble human temporal lobe epileptic activity.

  20. Tactile Experience Induces c-fos Expression in Rat Barrel Cortex

    PubMed Central

    Filipkowski, Robert K.; Rydz, Marek; Berdel, Bozena; Morys, Janusz; Kaczmarek, Leszek

    2000-01-01

    Understanding gene expression that is responsive to sensory stimulation is central to elucidate molecular mechanisms underlying neuronal plasticity. In this study we demonstrate two new methods of stimulating whiskers that provide major sensory input to rat neocortex. In the first paradigm, animals were placed on the top of a cylinder and their vibrissae were brushed by hand. In the second paradigm, animals were placed for a brief period of time into a new, wired cage resulting in vibrissae stimulation when they explored the new environment. Both approaches induced c-Fos expression in barrel cortex corresponding to the stimulated vibrissae, especially in layer IV. Layers II/III and V/VI also showed c-Fos induction, but there were no detectable changes in layer VIb. The majority of c-Fos-expressing cells are probably not inhibitory neurons, because they do not show parvalbumin staining. Both paradigms, in contrast to the previous methods, are simple to use and do not require anesthesia, restraint of animals, or elaborate experimental setups. PMID:10753978

  1. HDAC1 negatively regulates Bdnf and Pvalb required for parvalbumin interneuron maturation in an experience-dependent manner.

    PubMed

    Koh, Dawn X P; Sng, Judy C G

    2016-11-01

    During early postnatal development, neuronal circuits are sculpted by sensory experience provided by the external environment. This experience-dependent regulation of circuitry development consolidates the balance of excitatory-inhibitory (E/I) neurons in the brain. The cortical barrel-column that innervates a single principal whisker is used to provide a clear reference frame for studying the consolidation of E/I circuitry. Sensory deprivation of S1 at birth disrupts the consolidation of excitatory-inhibitory balance by decreasing inhibitory transmission of parvalbumin interneurons. The molecular mechanisms underlying this decrease in inhibition are not completely understood. Our findings show that epigenetic mechanisms, in particular histone deacetylation by histone deacetylases, negatively regulate the expression of brain-derived neurotrophic factor (Bdnf) and parvalbumin (Pvalb) genes during development, which are required for the maturation of parvalbumin interneurons. After whisker deprivation, increased histone deacetylase 1 expression and activity led to increased histone deacetylase 1 binding and decreased histone acetylation at Bdnf promoters I-IV and Pvalb promoter, resulting in the repression of Bdnf and Pvalb gene transcription. The decrease in Bdnf expression further affected parvalbumin interneuron maturation at layer II/III in S1, demonstrated by decreased parvalbumin expression, a marker for parvalbumin interneuron maturation. Knockdown of HDAC1 recovered Bdnf and Pvalb gene transcription and also prevented the decrease of inhibitory synapses accompanying whisker deprivation.

  2. Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice.

    PubMed

    Darvish-Ghane, Soroush; Yamanaka, Manabu; Zhuo, Min

    2016-01-01

    Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA.

  3. Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia

    PubMed Central

    Hamburg, Hannah; Trossbach, Svenja V.; Bader, Verian; Chwiesko, Caroline; Kipar, Anja; Sauvage, Magdalena; Crum, William R.; Vernon, Anthony C.; Bidmon, Hans J.; Korth, Carsten

    2016-01-01

    To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1), and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia. PMID:27721451

  4. Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs.

    PubMed Central

    Miedema, F; Petit, A J; Terpstra, F G; Schattenkerk, J K; de Wolf, F; Al, B J; Roos, M; Lange, J M; Danner, S A; Goudsmit, J

    1988-01-01

    To investigate the effect of persistent HIV infection on the immune system, we studied leukocyte functions in 14 asymptomatic homosexual men (CDC group II/III) who were at least two years seropositive, but who still had normal numbers of circulating CD4+ T cells. Compared with age-matched heterosexual men and HIV-negative homosexual men, the CD4+ and CD8+ T cells from seropositive men showed decreased proliferation to anti-CD3 monoclonal antibody and decreased CD4+ T-helper activity on PWM-driven differentiation of normal donor B cells. Monocytes of HIV-infected homosexual men showed decreased accessory function on normal T cell proliferation induced by CD3 monoclonal antibody. The most striking defect in leukocyte functional activities was observed in the B cells of HIV-infected men. B cells of 13 out of 14 seropositive men failed to produce Ig in response to PWM in the presence of adequate allogeneic T-helper activity. These findings suggest that HIV induces severe immunological abnormalities in T cells, B cells, and antigen-presenting cells early in infection before CD4+ T cell numbers start to decline. Impaired immunological function in subclinically HIV-infected patients may have clinical implications for vaccination strategies, in particular the use of live vaccines in groups with a high prevalence of HIV seropositivity. PMID:2974045

  5. Effects of perinatal undernutrition on the basilar dendritic arbor of the anterior cingulate pyramidal neurons in lactating dams.

    PubMed

    Salas, Manuel; Torrero, Carmen; Regalado, Mirelta; Rubio, Lorena

    2015-01-01

    In altricial species, early pre- and neonatal undernutrition interferes with the neuronal organization of several brain structures that have critical time windows for synaptic organization, including the prefrontal cortex. In Golgi-Cox stained tissue the basilar dendritic arbor of pyramidal neurons in the anterior cingulate cortex of early underfed adult lactating dams was evaluated. The anterior cingulate of the rat plays a major role in the execution of sexual, maternal and visual attentional control and other cognitive responses. The effects of neonatal undernutrition on the basilar dendritic tree and perikaryon measurements in layer II/III pyramidal neurons of the anterior cingulate were examined in lactating dams at postpartum days 8 and 12. In the underfed dams the distal portions of the basilar dendrites had fewer branches and a lower dendritic density of dendrites, and neurons had perikarya with reduced perimeter and cross-sectional area. Thus, the neuronal alterations may interfere the plastic synaptic activity and with maternal cognitive performance of rats subjected to early underfeeding. These anatomical alterations of the anterior cingulate may help to understand the disruption of long-term cognitive processes associated with perinatal food restriction.

  6. [Relation between biomarkers of the coagulation cascade, fibrinolytic system and lipid profiles in hypertensive patients with various coagulation potential of whole blood].

    PubMed

    Tolstopiatov, S M

    2009-01-01

    227 hypertensive patients, stage II-III have been investigated using new laboratory technology (patent of Ukraine), to reveal signs of coagulation potential and fibrinolytic tests of whole blood. 120 patients have been observed to detect definite markers of lipid profile. Obtained results revealed depression of fibrinolysis (from I to X degree) in 77.3%, hypercoagulation in 53.3%, and hypocoagulation in 25.6% of patients. These multidirectional changes proves the necessity of a laboratory control during administration of antiplatelets drugs. Besides, having coagulation module (CM) at VI-VIII degree, which corresponds to a high clinical risk factor of and urgent situation, the tactics of the treatment should be aggressive and parenteral. Lipid concentration was considerably higher at hypercoagulation state, although in 11-22% of cases, dislipidemia developed at hypocoagulation state. Total cholesterol (TC) and lipoprotein levels do not influence on formation of blood clot and considerably increase its density (P < 0.01), that complicates dissolving of blood clot by the fibrinolytic system, functional state of which goes down additionally during the increase of TC (r = -0.207; P < 0.05) and LDL (r = -0.197; P < 0.05). Fibrinolytic activity has strongly correlated with clot level (r = -0.465; P < 0.0001) and its density (r = -0.393; P < 0.0001). So, the algorithm of an individual treatment should include antihypertensive (under the control Blood Pressure), antiliplatelets (under the control MC) and hypolipidemic (under the laboratory control) agents.

  7. A review of the use of trastuzumab (Herceptin) plus vinorelbine in metastatic breast cancer.

    PubMed

    Chan, A

    2007-07-01

    The combination of trastuzumab (Herceptin) and vinorelbine (Navelbine) in the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is valuable for several reasons. There is proven synergism of these agents in preclinical models, both agents are well tolerated and there is minimal overlapping toxicity. This article reviews clinical experience with trastuzumab and vinorelbine from phase II/III trials including >450 assessable patients. Results across the trials show objective response rates for the combination in the range of 44%-86% (51%-86% as first-line treatment) and a median duration of response of 10-17.5 months. Approximately 50% of patients experience grade 3/4 neutropenia, which is of short duration and manageable. Symptomatic cardiac events are infrequent (seven episodes of grade 3 toxicity across all trials). Overall, trastuzumab-vinorelbine combination therapy offers patients with HER2-positive MBC, an effective and well-tolerated treatment that is suitable for prolonged duration of use.

  8. Local cerebral glucose utilization in the neocortical areas of the rat brain.

    PubMed

    Wree, A; Zilles, K; Schleicher, A

    1990-01-01

    The neocortex of the rat brain can be subdivided into regions of different local cerebral glucose utilization (LCGU). However, only a few neocortical areas can be delineated by differences in mean LCGUs between neighbouring areas. These area borders correspond exactly with cytoarchitectonically defined borders found in adjacent Nissl-stained preparations. On the other hand, nearly all of the architectonically defined area borders are also recognizable in the LCGU pictures, if differences in laminar distribution patterns of LCGU are taken into account. Furthermore, interareal differences in mean LCGU mainly reflect changes in layer IV, whereas layers II-III and V-VI show nearly identical LCGU values in all neocortical areas of the rat brain. The primary sensory areas exhibit the highest LCGU in layer IV, while the primary motor cortex shows a high LCGU in layer V. As the cytoarchitectonically defined pattern of the cortex is generally corroborated by the regional and laminar LCGU distribution, anatomical, metabolic and functional aspects of cortical architecture are associated.

  9. The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment.

    PubMed Central

    Green, Daniel; Pace, Suzi; Curtis, Suzanne M; Sakowska, Magdalena; Lamb, Graham D; Dulhunty, Angela F; Casarotto, Marco G

    2003-01-01

    An alpha-helical II-III loop segment of the dihydropyridine receptor activates the ryanodine receptor calcium-release channel. We describe a novel manipulation in which this agonist's activity is increased by modifying its surface structure to resemble that of a toxin molecule. In a unique system, native beta-sheet scorpion toxins have been reported to activate skeletal muscle ryanodine receptor calcium channels with high affinity by binding to the same site as the lower-affinity alpha-helical dihydropyridine receptor segment. We increased the alignment of basic residues in the alpha-helical peptide to mimic the spatial orientation of active residues in the scorpion toxin, with a consequent 2-20-fold increase in the activity of the alpha-helical peptide. We hypothesized that, like the native peptide, the modified peptide and the scorpion toxin may bind to a common site. This was supported by (i) similar changes in ryanodine receptor channel gating induced by the native or modified alpha-helical peptide and the beta-sheet toxin, a 10-100-fold reduction in channel closed time, with a < or = 2-fold increase in open dwell time and (ii) a failure of the toxin to further activate channels activated by the peptides. These results suggest that diverse structural scaffolds can present similar conformational surface properties to target common receptor sites. PMID:12429019

  10. Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats.

    PubMed

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I-III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α , and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I-III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α , and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients.

  11. Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats.

    PubMed

    Macedo, Levy W; Cararo, José H; Maravai, Soliany G; Gonçalves, Cinara L; Oliveira, Giovanna M T; Kist, Luiza W; Guerra Martinez, Camila; Kurtenbach, Eleonora; Bogo, Maurício R; Hipkiss, Alan R; Streck, Emilio L; Schuck, Patrícia F; Ferreira, Gustavo C

    2016-10-01

    Carnosine (β-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-γ coactivator 1-α (Ppargc1α), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders.

  12. Impairment of Electron Transfer Chain Induced by Acute Carnosine Administration in Skeletal Muscle of Young Rats

    PubMed Central

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I–III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α, and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I–III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α, and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  13. Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis?

    PubMed

    Iqbal, Javeed; Naushad, Hina; Bi, Chengfeng; Yu, Jiayu; Bouska, Alyssa; Rohr, Joseph; Chao, Wang; Fu, Kai; Chan, Wing C; Vose, Julie M

    2016-03-01

    Current genomic technologies have immensely improved disease classification and prognostication of major subtypes of B-cell lymphomas. This novel genetic information has not only aided in diagnosis, but has also revealed a landscape of critical molecular events that determine the biological and clinical behavior of a lymphoma. In this review, we summarized the genetic characteristics of major subtypes of B-cell lymphomas, including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). We illustrated how genomic profiling had identified molecular subgroups in DLBCL with varied clinical outcomes, and how a subset of genes defined prognosis in MCL and aided in BL diagnoses. We also highlighted some Phase II/III clinical trials using new therapeutic agents to determine clinical efficacy in novel molecular subgroups with distinct gene expression patterns. We believe that refinement of genomic signatures will require more intensive efforts from the biomedical research community to improve targeted therapy designs and bring a substantial change in the treatment decisions. In the next era of genomic medicine, we anticipate that a clinically and biologically relevant molecular profile of each tumor will be obtained at diagnosis to guide therapy.

  14. Thermodynamics and mechanism studies on electrochemical removal of cesium ions from aqueous solution using a nanoparticle film of copper hexacyanoferrate.

    PubMed

    Chen, Rongzhi; Tanaka, Hisashi; Kawamoto, Tohru; Asai, Miyuki; Fukushima, Chikako; Kurihara, Masato; Ishizaki, Manabu; Watanabe, Masayuki; Arisaka, Makoto; Nankawa, Takuya

    2013-12-26

    Nanoparticle (NPs) film of copper hexacyanoferrate (CuHCF(III)) was developed for electrochemically cesium separation from wastewater. Different form the electro- or chemical deposited films, CuHCF(III) NPs were firstly covered with ferrocyanide anions, so that they can be well dispersed in water and formed ink. Then CuHCF(III) NPs can be uniformly coated by simple wet printing methods, so it is feasible to prepare NPs film of any sizes, or any patterns at low cost. This process provided a promising technology for preparing large scale electrodes for sequential removal of Cs from wastewater in the columns. Cs separation can be controlled by an electrically switched ion exchange (ESIX) system. Effect of temperatures, and ionic strength on Cs removal was investigated. Thermodynamics results showed that Cs adsorption process was exothermic in nature and favored at low temperature. Ionic strength study indicated the CuHCF(III) film can selectively separate Cs in wide ionic strength range from 1 × 10(-4) to 1 × 10(-1) M Na(+). XPS results demonstrated that the electrochemical oxidation-reduction of Fe (II/III) made contributions to Cs separation.

  15. Subthalamic nucleus - sensorimotor cortex functional connectivity in de novo and moderate Parkinson’s disease

    PubMed Central

    Kurani, A.S.; Seidler, R.D.; Burciu, R.G.; Comella, C.L.; Corcos, D.M.; Okun, M.S.; MacKinnon, C.D.; Vaillancourt, D.E.

    2014-01-01

    Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson’s disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is prior to when patients begin dopamine therapy. Resting state functional magnetic resonance imaging was carried out in 20 de novo (drug-naïve) patients with PD (HY stage: I-II), 19 patients with moderate PD (HY stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson’s Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and prior to dopamine therapy. PMID:25095723

  16. The impact of exercise on body composition and nutritional intake in patients with heart failure.

    PubMed

    Oka, Roberta K; Sanders, Mark G

    2005-01-01

    Little is known about the nutritional status of heart failure patients and the potential synergistic effects between nutritional intake and exercise. This small, randomized trial examined the effects of a 3-month exercise program on body composition and nutritional intake in 31 men (17 exercisers; 14 controls), aged 30-76 years (mean, 56 years) with stable class II-III heart failure. Baseline and 3-month evaluations included body mass index, body fat mass by triceps skinfold thickness, dietary intake by food frequency questionnaire, and the 6-minute walk test. Exercise consisted of walking 3 d/wk and resistance exercises 2 d/wk for 40-60 minutes. Dietary recommendations were consistent with the American Heart Association/American College of Cardiology heart failure guidelines. Exercisers decreased body weight (p=0.001), body mass index (p=0.0001), and triceps skinfold thickness (p=0.03) and improved 6-minute walk test (p=0.01) compared with controls. Exercisers also demonstrated trends toward decreased total caloric and cholesterol intake and a three-fold higher carbohydrate, fiber, and beta carotene intake vs. controls. In this study population, protein, fiber, and magnesium intake were below recommended daily allowance. After exercise, body mass index was reduced, accompanied by dietary modifications including greater intake of foods with higher moisture content. Further study is needed to investigate the interaction among diet, exercise, and weight.

  17. Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation

    PubMed Central

    Kobayashi, Katsuya; Matsumoto, Riki; Matsuhashi, Masao; Usami, Kiyohide; Shimotake, Akihiro; Kunieda, Takeharu; Kikuchi, Takayuki; Mikuni, Nobuhiro; Miyamoto, Susumu; Fukuyama, Hidenao; Takahashi, Ryosuke; Ikeda, Akio

    2015-01-01

    Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFASEP(N20) and HFASEP(N80)) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFACCEP(N1) and HFACCEP(N2)). HFASEP(N20) showed the power peak in the frequency above 200 Hz, while HFACCEP(N1) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFACCEP(N1) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions. PMID:26087042

  18. Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

    PubMed Central

    Dunne, Philip D.; O'Reilly, Paul G.; Coleman, Helen G.; Gray, Ronan T.; Longley, Daniel B.; Johnston, Patrick G.; Salto-Tellez, Manuel

    2016-01-01

    The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four consensus molecular subtypes (CMS's) representing the underlying biology in CRC. The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis in early stage disease, but paradoxically has the worst prognosis following relapse, suggesting the presence of factors enabling neoplastic cells to circumvent this immune response. To identify the genes influencing subsequent poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse. In a cohort of early stage colon cancer (n=460), we examined, in silico, changes in gene expression within the CMS1 subtype and demonstrated for the first time the favorable prognostic value of chemokine-like factor (CKLF) gene expression in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using transcription profiles originating from cell sorted CRC tumors, we delineated the source of CKLF transcription within the colorectal tumor microenvironment to the leukocyte component of these tumors. Further to this, we confirmed that CKLF gene expression is confined to distinct immune subsets in whole blood samples and primary cell lines, highlighting CKLF as a potential immune cell-derived factor promoting tumor immune-surveillance of nascent neoplastic cells, particularly in CMS1 tumors. Building on the recently reported CRCSC data, we provide compelling evidence that leukocyte-infiltrate derived CKLF expression is a candidate biomarker of favorable prognosis, specifically in MSI-immune stage II/III disease. PMID:27153559

  19. Indications for cardiac resynchronization therapy: 2011 update from the Heart Failure Society of America Guideline Committee.

    PubMed

    Stevenson, William G; Hernandez, Adrian F; Carson, Peter E; Fang, James C; Katz, Stuart D; Spertus, John A; Sweitzer, Nancy K; Tang, W H Wilson; Albert, Nancy M; Butler, Javed; Westlake Canary, Cheryl A; Collins, Sean P; Colvin-Adams, Monica; Ezekowitz, Justin A; Givertz, Michael M; Hershberger, Ray E; Rogers, Joseph G; Teerlink, John R; Walsh, Mary N; Stough, Wendy Gattis; Starling, Randall C

    2012-02-01

    Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (≥150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of ≥120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials.

  20. Modulation of NMDA and AMPA-mediated synaptic transmission by CB1 receptors in frontal cortical pyramidal cells.

    PubMed

    Li, Qiang; Yan, Haidun; Wilson, Wilkie A; Swartzwelder, H Scott

    2010-06-25

    Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor-mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutamatergic activity by CB1 receptors in the frontal neocortex is mediated by a presynaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function.

  1. Avian Magnetoreception: Elaborate Iron Mineral Containing Dendrites in the Upper Beak Seem to Be a Common Feature of Birds

    PubMed Central

    Falkenberg, Gerald; Fleissner, Gerta; Schuchardt, Kirsten; Kuehbacher, Markus; Thalau, Peter; Mouritsen, Henrik; Heyers, Dominik; Wellenreuther, Gerd; Fleissner, Guenther

    2010-01-01

    The magnetic field sensors enabling birds to extract orientational information from the Earth's magnetic field have remained enigmatic. Our previously published results from homing pigeons have made us suggest that the iron containing sensory dendrites in the inner dermal lining of the upper beak are a candidate structure for such an avian magnetometer system. Here we show that similar structures occur in two species of migratory birds (garden warbler, Sylvia borin and European robin, Erithacus rubecula) and a non-migratory bird, the domestic chicken (Gallus gallus). In all these bird species, histological data have revealed dendrites of similar shape and size, all containing iron minerals within distinct subcellular compartments of nervous terminals of the median branch of the Nervus ophthalmicus. We also used microscopic X-ray absorption spectroscopy analyses to identify the involved iron minerals to be almost completely Fe III-oxides. Magnetite (Fe II/III) may also occur in these structures, but not as a major Fe constituent. Our data suggest that this complex dendritic system in the beak is a common feature of birds, and that it may form an essential sensory basis for the evolution of at least certain types of magnetic field guided behavior. PMID:20169083

  2. Single-unit activity in piriform cortex during slow-wave state is shaped by recent odor experience.

    PubMed

    Wilson, Donald A

    2010-02-03

    Memory and its underlying neural plasticity play important roles in sensory discrimination and cortical pattern recognition in olfaction. Given the reported function of slow-wave sleep states in neocortical and hippocampal memory consolidation, we hypothesized that activity during slow-wave states within the piriform cortex may be shaped by recent olfactory experience. Rats were anesthetized with urethane and allowed to spontaneously shift between slow-wave and fast-wave states as recorded in local field potentials within the anterior piriform cortex. Single-unit activity of piriform cortical layer II/III neurons was recorded simultaneously. The results suggest that piriform cortical activity during slow-wave states is shaped by recent (several minutes) odor experience. The temporal structure of single-unit activity during slow waves was modified if the animal had been stimulated with an odor within the receptive field of that cell. If no odor had been delivered, the activity of the cell during slow-wave activity was stable across the two periods. The results demonstrate that piriform cortical activity during slow-wave state is shaped by recent odor experience, which could contribute to odor memory consolidation.

  3. Dry eye syndrome among computer users

    NASA Astrophysics Data System (ADS)

    Gajta, Aurora; Turkoanje, Daniela; Malaescu, Iosif; Marin, Catalin-Nicolae; Koos, Marie-Jeanne; Jelicic, Biljana; Milutinovic, Vuk

    2015-12-01

    Dry eye syndrome is characterized by eye irritation due to changes of the tear film. Symptoms include itching, foreign body sensations, mucous discharge and transitory vision blurring. Less occurring symptoms include photophobia and eye tiredness. Aim of the work was to determine the quality of the tear film and ocular dryness potential risk in persons who spend more than 8 hours using computers and possible correlations between severity of symptoms (dry eyes symptoms anamnesis) and clinical signs assessed by: Schirmer test I, TBUT (Tears break-up time), TFT (Tear ferning test). The results show that subjects using computer have significantly shorter TBUT (less than 5 s for 56 % of subjects and less than 10 s for 37 % of subjects), TFT type II/III in 50 % of subjects and type III 31% of subjects was found when compared to computer non users (TFT type I and II was present in 85,71% of subjects). Visual display terminal use, more than 8 hours daily, has been identified as a significant risk factor for dry eye. It's been advised to all persons who spend substantial time using computers to use artificial tears drops in order to minimize the symptoms of dry eyes syndrome and prevents serious complications.

  4. Massive thyroxine intoxication: evaluation of plasma extraction.

    PubMed

    Binimelis, J; Bassas, L; Marruecos, L; Rodriguez, J; Domingo, M L; Madoz, P; Armengol, S; Mangues, M A; de Leiva, A

    1987-01-01

    Six patients were admitted after erroneous massive intake of levothyroxine (70-1200 mg over an interval of 2-12 days). All patients developed classical symptoms of thyrotoxicosis within 3 days of the first dose; five patients presented grade II-III coma and one became stuporous (days 7-10). Two patients developed left ventricular failure and three had arrhythmias (days 8-11). Total thyroid hormone levels in serum on admission ranged 935-7728 nmol/l for T4 (TT4) and 23-399 nmol/l for T3 (TT3). All patients received treatment with hydrocortisone and Propranolol. Propylthiouracil was also given in 3 cases. Extractive techniques (charcoal haemoperfusion and/or plasmapheresis) were initiated 8-14 days after the first dose of L-T4. The plasma disappearance rate (K) of TT4 with plasmapheresis was 30 times higher, on average, than under standard medical treatment (M). Also, K of TT4 under haemoperfusion was about five times higher than K under M. K changes for TT3 were higher under haemoperfusion than under plasmapheresis. Furthermore, extractive procedures shortened the average half life of TT4, (from 106.5 +/- 44.6 to 59.7 +/- 20.2 h, p less than 0.05).

  5. Treatment with tianeptine induces antidepressive-like effects and alters the neurotrophin levels, mitochondrial respiratory chain and cycle Krebs enzymes in the brain of maternally deprived adult rats.

    PubMed

    Della, Franciela P; Abelaira, Helena M; Réus, Gislaine Z; Santos, Maria Augusta B dos; Tomaz, Débora B; Antunes, Altamir R; Scaini, Giselli; Morais, Meline O S; Streck, Emilio L; Quevedo, João

    2013-03-01

    Maternally deprived rats were treated with tianeptine (15 mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming and open field tests. The BDNF, NGF and energy metabolism were assessed in the rat brain. Deprived rats increased the immobility time, but tianeptine reversed this effect and increased the swimming time; the BDNF levels were decreased in the amygdala of the deprived rats treated with saline and the BDNF levels were decreased in the nucleus accumbens within all groups; the NGF was found to have decreased in the hippocampus, amygdala and nucleus accumbens of the deprived rats; citrate synthase was increased in the hippocampus of non-deprived rats treated with tianeptine and the creatine kinase was decreased in the hippocampus and amygdala of the deprived rats; the mitochondrial complex I and II-III were inhibited, and tianeptine increased the mitochondrial complex II and IV in the hippocampus of the non-deprived rats; the succinate dehydrogenase was increased in the hippocampus of non-deprived rats treated with tianeptine. So, tianeptine showed antidepressant effects conducted on maternally deprived rats, and this can be attributed to its action on the neurochemical pathways related to depression.

  6. Identification of the CRP regulon using in vitro and in vivo transcriptional profiling.

    PubMed

    Zheng, Dongling; Constantinidou, Chrystala; Hobman, Jon L; Minchin, Stephen D

    2004-01-01

    The Escherichia coli cyclic AMP receptor protein (CRP) is a global regulator that controls transcription initiation from more than 100 promoters by binding to a specific DNA sequence within cognate promoters. Many genes in the CRP regulon have been predicted simply based on the presence of DNA-binding sites within gene promoters. In this study, we have exploited a newly developed technique, run-off transcription/microarray analysis (ROMA) to define CRP-regulated promoters. Using ROMA, we identified 176 operons that were activated by CRP in vitro and 16 operons that were repressed. Using positive control mutants in different regions of CRP, we were able to classify the different promoters into class I or class II/III. A total of 104 operons were predicted to contain Class II CRP-binding sites. Sequence analysis of the operons that were repressed by CRP revealed different mechanisms for CRP inhibition. In contrast, the in vivo transcriptional profiles failed to identify most CRP-dependent regulation because of the complexity of the regulatory network. Analysis of these operons supports the hypothesis that CRP is not only a regulator of genes required for catabolism of sugars other than glucose, but also regulates the expression of a large number of other genes in E.coli. ROMA has revealed 152 hitherto unknown CRP regulons.

  7. What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

    PubMed Central

    Buzzard, Katherine A.; Broadley, Simon A.; Butzkueven, Helmut

    2012-01-01

    Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects. PMID:23202920

  8. Neuronal morphology in the African elephant (Loxodonta africana) neocortex.

    PubMed

    Jacobs, Bob; Lubs, Jessica; Hannan, Markus; Anderson, Kaeley; Butti, Camilla; Sherwood, Chet C; Hof, Patrick R; Manger, Paul R

    2011-01-01

    Virtually nothing is known about the morphology of cortical neurons in the elephant. To this end, the current study provides the first documentation of neuronal morphology in frontal and occipital regions of the African elephant (Loxodonta africana). Cortical tissue from the perfusion-fixed brains of two free-ranging African elephants was stained with a modified Golgi technique. Neurons of different types (N=75), with a focus on superficial (i.e., layers II-III) pyramidal neurons, were quantified on a computer-assisted microscopy system using Neurolucida software. Qualitatively, elephant neocortex exhibited large, complex spiny neurons, many of which differed in morphology/orientation from typical primate and rodent pyramidal neurons. Elephant cortex exhibited a V-shaped arrangement of bifurcating apical dendritic bundles. Quantitatively, the dendrites of superficial pyramidal neurons in elephant frontal cortex were more complex than in occipital cortex. In comparison to human supragranular pyramidal neurons, elephant superficial pyramidal neurons exhibited similar overall basilar dendritic length, but the dendritic segments tended to be longer in the elephant with less intricate branching. Finally, elephant aspiny interneurons appeared to be morphologically consistent with other eutherian mammals. The current results thus elaborate on the evolutionary roots of Afrotherian brain organization and highlight unique aspects of neural architecture in elephants.

  9. Prickly business. The finer points of acupuncture.

    PubMed

    Chavez, C

    1995-01-01

    Acupuncture, which is gaining credibility among the Western medical establishment, is just one element of traditional Chinese medicine (TCM) being used to treat fatigue, nausea, insomnia, diarrhea, menstrual problems, and HIV-related peripheral neuropathy. Acupuncture is often used in combination with exercise massage, meditation, and herbal therapy. Special combinations of Chinese herbs are used to treat HIV-conditions, promote digestion, increase energy, and fight fungal infections. "Enhance", "Resist", and "Combination A", are three such formulas. Another benefit of acupuncture and Chinese herbs is their ability to decrease side effects associated with Western medicine. The growing medical interest in acupuncture is evidenced in the progress of CPCRA 022, a phase II/III trial to study acupuncture alone or in combination with amitriptyline, an anti-depressant, as a treatment for peripheral neuropathy. The National Institutes of Health (NIH) recently awarded the Bastyr University in Seattle, with funds to study alternative therapies. Regardless of outcomes, these studies may encourage other organizations to pursue acupuncture trials.

  10. Methylphenidate Decreases ATP Levels and Impairs Glutamate Uptake and Na(+),K(+)-ATPase Activity in Juvenile Rat Hippocampus.

    PubMed

    Schmitz, Felipe; Pierozan, Paula; Rodrigues, André F; Biasibetti, Helena; Grings, Mateus; Zanotto, Bruna; Coelho, Daniella M; Vargas, Carmen R; Leipnitz, Guilhian; Wyse, Angela T S

    2016-11-14

    The study of the long-term neurological consequences of early exposure with methylphenidate (MPH) is very important since this psychostimulant has been widely misused by children and adolescents who do not meet full diagnostic criteria for ADHD. The aim of this study was to examine the effect of early chronic exposure with MPH on amino acids profile, glutamatergic and Na(+),K(+)-ATPase homeostasis, as well as redox and energy status in the hippocampus of juvenile rats. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 45th day of age. Results showed that MPH altered amino acid profile in the hippocampus, decreasing glutamine levels. Glutamate uptake and Na(+),K(+)-ATPase activity were decreased after chronic MPH exposure in the hippocampus of rats. No changes were observed in the immunocontents of glutamate transporters (GLAST and GLT-1), and catalytic subunits of Na(+),K(+)-ATPase (α1, α2, and α3), as well as redox status. Moreover, MPH provoked a decrease in ATP levels in the hippocampus of chronically exposed rats, while citrate synthase, succinate dehydrogenase, respiratory chain complexes activities (II, II-III, and IV), as well as mitochondrial mass and mitochondrial membrane potential were not altered. Taken together, our results suggest that chronic MPH exposure at early age impairs glutamate uptake and Na(+),K(+)-ATPase activity probably by decreasing in ATP levels observed in rat hippocampus.

  11. Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences.

    PubMed

    Toscani, Siro; Céolin, René; Minassian, Léon Ter; Barrio, Maria; Veglio, Nestor; Tamarit, Josep-Lluis; Louër, Daniel; Rietveld, Ivo B

    2016-01-30

    The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements.

  12. Toward Head-Up and Head-Worn Displays for Equivalent Visual Operations

    NASA Technical Reports Server (NTRS)

    Prinzel, Lawrence J., III; Arthur, Jarvis J.; Bailey, Randall E.; Shelton, Kevin J.; Kramer, Lynda J.; Jones, Denise R.; Williams, Steven P.; Harrison, Stephanie J.; Ellis, Kyle K.

    2015-01-01

    A key capability envisioned for the future air transportation system is the concept of equivalent visual operations (EVO). EVO is the capability to achieve the safety of current-day Visual Flight Rules (VFR) operations and maintain the operational tempos of VFR irrespective of the weather and visibility conditions. Enhanced Flight Vision Systems (EFVS) offer a path to achieve EVO. NASA has successfully tested EFVS for commercial flight operations that has helped establish the technical merits of EFVS, without reliance on natural vision, to runways without category II/III ground-based navigation and lighting requirements. The research has tested EFVS for operations with both Head-Up Displays (HUDs) and "HUD equivalent" Head-Worn Displays (HWDs). The paper describes the EVO concept and representative NASA EFVS research that demonstrate the potential of these technologies to safely conduct operations in visibilities as low as 1000 feet Runway Visual Range (RVR). Future directions are described including efforts to enable low-visibility approach, landing, and roll-outs using EFVS under conditions as low as 300 feet RVR.

  13. Sulfate radical-induced degradation of Acid Orange 7 by a new magnetic composite catalyzed peroxymonosulfate oxidation process.

    PubMed

    Chen, Dan; Ma, Xiaolong; Zhou, Jizhi; Chen, Xi; Qian, Guangren

    2014-08-30

    We synthesized a novel magnetic composite, Fe3O4/Cu(Ni)Cr-LDH, as a heterogeneous catalyst for the degradation of organic dyes in the solution using sulfate radical-based advanced oxidation processes. The physicochemical properties of the composite synthesized via two-step microwave hydrothermal method were characterized by several techniques, such as X-ray diffraction (XRD), inductively coupled plasma (ICP), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The degradation tests were performed at 25°C with Acid Orange 7 (AO7) initial concentration of 25mg/L and AO7/peroxymonosulfate (PMS) molar ratio of 1:10, which showed that the complete degradation by Fe3O4/Cu1.5Ni0.5Cr-LDH could be achieved and the mineralization rate could reach 46%. PMS was activated by Cu (II) and Fe (II/III) of Fe3O4/Cu(Ni)Cr-LDH to generate sulfate radicals (SO4(-)). Subsequently, the organic functional groups of AO7 molecules were destroyed by sulfate radicals (SO4(-)), inducing the degradation of AO7. Moreover, the catalytic behavior of the catalysts could be reused five times. Therefore, our work suggested that the Fe3O4/Cu(Ni)Cr-LDH composite could be applied widely for the treatment of organic dyes in wastewater.

  14. The Role of Hypothermia Coordinator: A Case of Hypothermic Cardiac Arrest Treated with ECMO.

    PubMed

    Darocha, Tomasz; Kosinski, Sylweriusz; Moskwa, Maciej; Jarosz, Anna; Sobczyk, Dorota; Galazkowski, Robert; Slowik, Marcin; Drwila, Rafal

    2015-12-01

    We present a description of emergency medical rescue procedures in a patient suffering from severe hypothermia who was found in the Babia Gora mountain range (Poland). After diagnosing the symptoms of II/III stage hypothermia according to the Swiss Staging System, the Mountain Rescue Service notified the coordinator from the Severe Accidental Hypothermia Center (CLHG) Coordinator in Krakow and then kept in constant touch with him. In accordance with the protocol for managing such situations, the coordinator started the procedure for patients in severe hypothermia with the option of extracorporeal warming and secured access to a device for continuous mechanical chest compression. After reaching the hospital, extracorporeal warming with ECMO support in the arteriovenuous configuration was started. The total duration of circulatory arrest was 150 minutes. The rescue procedures were supervised by the coordinator, who was on 24-hour duty and was reached by means of an alarm phone. The task of the coordinator is to consult the management of hypothermia cases, use his knowledge and experience to help in the diagnosis and treatment. and if the need arises refer the patient for ECMO at CLHG. Good coordination, planning, predicting possible problems, and acting in accordance with the agreed procedures in the scheme, make it possible to shorten the time of reaching the destination hospital and implement effective treatment.

  15. Subthalamic nucleus--sensorimotor cortex functional connectivity in de novo and moderate Parkinson's disease.

    PubMed

    Kurani, Ajay S; Seidler, Rachael D; Burciu, Roxana G; Comella, Cynthia L; Corcos, Daniel M; Okun, Michael S; MacKinnon, Colum D; Vaillancourt, David E

    2015-01-01

    Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson's disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson's Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.

  16. Probability of success for phase III after exploratory biomarker analysis in phase II.

    PubMed

    Götte, Heiko; Kirchner, Marietta; Sailer, Martin Oliver

    2017-02-23

    The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs.

  17. HSV Recombinant Vectors for Gene Therapy

    PubMed Central

    Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

    2010-01-01

    The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID:20835362

  18. Therapeutic hypothermia for neonatal encephalopathy: a report from the first 3 years of the Baby Cooling Registry of Japan

    PubMed Central

    Tsuda, Kennosuke; Mukai, Takeo; Iwata, Sachiko; Shibasaki, Jun; Tokuhisa, Takuya; Ioroi, Tomoaki; Sano, Hiroyuki; Yutaka, Nanae; Takahashi, Akihito; Takeuchi, Akihito; Takenouchi, Toshiki; Araki, Yuko; Sobajima, Hisanori; Tamura, Masanori; Hosono, Shigeharu; Nabetani, Makoto; Iwata, Osuke; Adachi, Hiroyuki; Aiba, Satoru; Akiyoshi, Shinnosuke; Amizuka, Takasuke; Aoki, Mikihiro; Arai, Hirokazu; Arai, Junichi; Asanuma, Hideomi; Baba, Atsushi; Bonno, Motoki; Daimon, Yusuke; Egashira, Tomoko; Fukuhara, Rie; Fukushima, Naoki; Futamura, Masahide; Harada, Sayaka; Hattori, Tsukasa; Henmi, Nobuhide; Hiroma, Takehiko; Hisano, Tadashi; Ieda, Kuniko; Iida, Koichi; Iijima, Shigeo; Imai, Ken; Imamura, Takashi; Inoue, Shinkai; Ishiguro, Akio; Suzuki, Keiji; Ishii, Tsutomu; Ito, Takashi; Iwai, Masanori; Iwataki, Shinnichiro; Jinnai, Wataru; Kai, Akihiko; Kanbe, Taro; Kinoshita, Masahiro; Kanda, Hiroshi; Kaneko, Masatoshi; Kawase, Akihiko; Kawato, Hitoshi; Kida, Yoshikazu; Kihara, Minako; Kitano, Hiroyuki; Kishigami, Makoto; Shibata, Naoaki; Kito, Osamu; Kobayashi, Akira; Kohno, Yoshinori; Kokubo, Minoru; Kondo, Masatoshi; Konishi, Eri; Kugo, Masaki; Kouwaki, Masanori; Kumagai, Takeshi; Kusaka, Takashi; Kusuda, Takeshi; Maeda, Tomoki; Maede, Yoshinobu; Maji, Tomoaki; Makiya, Tomoko; Maruyama, Kennichi; Masunaga, Ken; Matsumoto, Atsushi; Matsumoto, Hiroshi; Matsumoto, Naoko; Mima, Aya; Minagawa, Kyoko; Minosaki, Yoshihiro; Minowa, Hideki; Miura, Mazumi; Miyata, Masafumi; Miyazono, Yayoi; Mizumoto, Hiroshi; Mori, Kazuhiro; Morioka, Ichiro; Morisawa, Takeshi; Nagaya, Ken; Nagayama, Yoshihisa; Naito, Atsushi; Nakamura, Kenji; Nakamura, Makoto; Nakao, Atsushi; Nakao, Hideto; Nakazawa, Yusuke; Nishimura, Yutaka; Nishizaki, Naoto; Nosaka, Kazuhiko; Nozaki, Masatoshi; Ochiai, Masayuki; Ohashi, Atsushi; Ohki, Shigeru; Omori, Isaku; Osone, Yoshiteru; Saito, Junko; Sato, Yoshiaki; Sato, Yoshitake; Seki, Kazuo; Shirakawa, Yoshitsugu; Shiro, Hiroyuki; Suzumura, Hiroshi; Takahashi, Ritsuko; Takahata, Yasushi; Taki, Atsuko; Tanaka, Taihei; Tateishi, Itaru; Tsunei, Mikio; Usuda, Touhei; Yada, Yukari; Yamamoto, Junko; Yamamoto, Masahito; Yoda, Hitoshi; Yokoi, Akiko; Yoshida, Shinobu; Yoshida, Taketoshi; Yoshida, Tomohide; Yoshikawa, Kayo

    2017-01-01

    Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012–2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were ≥36 weeks gestation and 99.4% weighed ≥1,800 g. Severe acidosis (pH < 7 or base deficit ≥16 mmol/L) was present in 68.9%, and 96.7% required resuscitation for >10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies. PMID:28051172

  19. Peak expiratory flow as a predictor for the effectiveness of sport for patients with COPD.

    PubMed

    Jungblut, S; Frickmann, H; Klingler, J; Zimmermann, B; Bargon, Joachim

    2006-01-31

    This study intended to find simple parameters that were able to determine the increase in physical performance as a result of sport in a group of patients with COPD (lung sport). We regularly investigated pulse, oxygenation and peak expiratory flow in participants with COPD of a "lung sport group", who participated in a structured weekly training program under professional supervision. Ten volunteers (7 females, 3 males, median of age = 69) with COPD (grade II-III) took part in the study. - The relative changes after 3 and 6 months were compared with the values of the first month of exercise. Measurements were carried out before exercise, after stamina training and at the end of the program. - Pulse and oxygenation did not show any changes. However, there was a significant improvement of peak flow after 6 months. - These peak flow changes represent further evidence of positive effects of sport in COPD and provide a parameter which allows the patients themselves to measure and evaluate the success of their physical activity.

  20. Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells

    PubMed Central

    Birkenkamp-Demtroder, K; Maghnouj, A; Mansilla, F; Thorsen, K; Andersen, C L; Øster, B; Hahn, S; Ørntoft, T F

    2011-01-01

    Background: The KIAA1199 transcript is upregulated in colon adenomas and downregulated upon β-catenin knockdown. Methods: Transcript profiling was performed on >500 colon biopsies, methylation profiling data were compared with transcript data. Immunohistochemistry assessed KIAA1199 protein expression in 270 stage II/III tumours (>3 years follow-up). The effects of stable KIAA1199 knockdown in SW480 cells (three different constructs) were studied using transcriptional profiling, proliferation and protein analysis. Results: The KIAA1199 transcript was strongly upregulated in 95% of adenocarcinomas. Absent expression in normal mucosa correlated with KIAA1199 promotor methylation. Nuclear and cytoplasmic KIAA1199 protein expression was identified in colon adenocarcinomas and other types of cancers. A subpopulation of patients with tumours strongly expressing KIAA1199 in the nucleus showed a better outcome with regard to recurrence as lung or liver metastases. The KIAA1199 knockdown affected the cell cycle and the Wnt-signalling pathway. Reduced cellular proliferation and decreased KI67, phosphorylated retinoblastoma, β-catenin and ASCL2 protein expression supported these findings. Eighteen Wnt-signalling genes differentially expressed upon KIAA1199 knockdown correlated with the KIAA1199 expression profile in clinical specimens. Conclusion: The KIAA1199 knockdown attenuates the effects of the Wnt/β-catenin signalling and it may thus be regarded as a regulatory part of this pathway. PMID:21772334

  1. Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

    PubMed Central

    Asencio, Claudio; Rodríguez-Hernandez, María A; Briones, Paz; Montoya, Julio; Cortés, Ana; Emperador, Sonia; Gavilán, Angela; Ruiz-Pesini, Eduardo; Yubero, Dèlia; Montero, Raquel; Pineda, Mercedes; O'Callaghan, María M; Alcázar-Fabra, María; Salviati, Leonardo; Artuch, Rafael; Navas, Plácido

    2016-01-01

    Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders. PMID:26014431

  2. Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content.

    PubMed

    Asencio, Claudio; Rodríguez-Hernandez, María A; Briones, Paz; Montoya, Julio; Cortés, Ana; Emperador, Sonia; Gavilán, Angela; Ruiz-Pesini, Eduardo; Yubero, Dèlia; Montero, Raquel; Pineda, Mercedes; O'Callaghan, María M; Alcázar-Fabra, María; Salviati, Leonardo; Artuch, Rafael; Navas, Plácido

    2016-03-01

    Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.

  3. Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial

    PubMed Central

    Snoeck-Stroband, Jiska B.; Lapperre, Therese S.; Sterk, Peter J.; Hiemstra, Pieter S.; Thiadens, Henk A.; Boezen, H. Marike; ten Hacken, Nick H. T.; Kerstjens, Huib A. M.; Postma, Dirkje S.; Timens, Wim; Sont, Jacob K.

    2015-01-01

    Background The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD. Methods Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30–80% of predicted, compatible with GOLD stages II-III), age 45–75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study. Results Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04). Conclusions Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD. Trial Registration ClinicalTrials.gov NCT00158847 PMID:26659582

  4. Unilateral blood flow decrease induces bilateral and symmetric responses in the immature brain.

    PubMed

    Villapol, Sonia; Bonnin, Philippe; Fau, Sébastien; Baud, Olivier; Renolleau, Sylvain; Charriaut-Marlangue, Christiane

    2009-11-01

    The effects of hemodynamic changes in the developing brain have yet to be fully understood. The aim of this study was to explore the relationship between perturbations of the cerebral blood flow in the developing brain via unilateral hypoperfusion in P7 rats. As expected, nuclear caspase-3 (casp3) cleavage and DNA fragmentation were detected at 48 hours after stroke in the injured cortex. Surprisingly, casp3 was also cleaved in the contralateral cortex, although without cell death markers. Delayed (48 hours) casp3 cleavage without DNA fragmentation was also identified after unilateral common carotid artery occlusion, both in the hypoperfused cortex and the unaffected cortex, producing mirror images. Upstream calpain activation, caspase-2 cleavage, and mitochondrial cytochrome c release initiated casp3 cleavage, but did not produce preconditioning. The neuronal marker NeuN co-localized with cleaved casp3 in cortical layers II-III and VI and with gaba-amino butyric acid in layer III. Indeed, collateral supply was provided from the opposite side during carotid artery occlusion but not after reperfusion, and the number of cleaved casp3-positive cells significantly negatively correlated with the common carotid artery immediate reperfusion percentage. In summary, unilateral hypoperfusion, while insufficient to induce cell death, may active bilateral and symmetric casp3 in the P7 rat brain. Additionally, the opposite healthy hemisphere is altered due to the injury and thus should not be used as an internal control.

  5. Patient-specific quantification of respiratory motion-induced dose uncertainty for step-and-shoot IMRT of lung cancer

    SciTech Connect

    Li, Heng; Park, Peter; Liu, Wei; Matney, Jason; Balter, Peter; Zhang, Xiaodong; Li, Xiaoqiang; Zhu, X. Ronald; Liao, Zhongxing; Li, Yupeng

    2013-12-15

    Purpose: The objective of this study was to quantify respiratory motion-induced dose uncertainty at the planning stage for step-and-shoot intensity-modulated radiation therapy (IMRT) using an analytical technique.Methods: Ten patients with stage II/III lung cancer who had undergone a planning four-dimensional (4D) computed tomographic scan and step-and-shoot IMRT planning were selected with a mix of motion and tumor size for this retrospective study. A step-and-shoot IMRT plan was generated for each patient. The maximum and minimum doses with respiratory motion were calculated for each plan, and the mean deviation from the 4D dose was calculated, taking delivery time, fractionation, and patient breathing cycle into consideration.Results: For all patients evaluated in this study, the mean deviation from the 4D dose in the planning target volume (PTV) was <2.5%, with a standard deviation <1.2%, and maximum point dose variation from the 4D dose was <6.2% in the PTV assuming delivery dose rate of 200 MU/min and patient breathing cycle of 8 s. The motion-induced dose uncertainty is a function of motion, fractionation, MU (plan modulation), dose rate, and patient breathing cycle.Conclusions: Respiratory motion-induced dose uncertainty varies from patient to patient. Therefore, it is important to evaluate the dose uncertainty on a patient-specific basis, which could be useful for plan evaluation and treatment strategy determination for selected patients.

  6. Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation.

    PubMed

    Kobayashi, Katsuya; Matsumoto, Riki; Matsuhashi, Masao; Usami, Kiyohide; Shimotake, Akihiro; Kunieda, Takeharu; Kikuchi, Takayuki; Mikuni, Nobuhiro; Miyamoto, Susumu; Fukuyama, Hidenao; Takahashi, Ryosuke; Ikeda, Akio

    2015-01-01

    Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFA(SEP(N20)) and HFA(SEP(N80))) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFA(CCEP(N1)) and HFA(CCEP(N2))). HFA(SEP(N20)) showed the power peak in the frequency above 200 Hz, while HFA(CCEP(N1)) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFA(CCEP(N1)) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.

  7. Glutamatergic Nonpyramidal Neurons From Neocortical Layer VI and Their Comparison With Pyramidal and Spiny Stellate Neurons

    PubMed Central

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L.; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-01-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription–polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity. PMID:19052106

  8. Glutamatergic nonpyramidal neurons from neocortical layer VI and their comparison with pyramidal and spiny stellate neurons.

    PubMed

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-02-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription-polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity.

  9. Use of the Child Engagement in Daily Life and Ease of Caregiving for Children to Evaluate Change in Young Children with Cerebral Palsy.

    PubMed

    Palisano, Robert J; Chiarello, Lisa A; McCoy, Sarah Westcott; Bartlett, Doreen; An, Mihee

    2014-08-28

    ABSTRACT Aims: Participation in family and recreational activities, self-care, and parent ease of caregiving are important outcomes for young children with cerebral palsy (CP). The aim of this study was to examine use of the Child Engagement in Daily Life and the Ease of Caregiving for Children to measure change over time. Methods: A convenience sample of 387 parents of young children with CP (18 months to 5 years of age) completed the measures twice, a mean of 12.7 months apart. Results: For the Child Engagement in Daily Life, parents of children in Gross Motor Function Classification System level I and levels II-III reported more change for the Self-care domain (medium effect) than the Family and Recreational Activities domain (small effect) and the Ease of Caregiving for Children (small effect). The change reported by parents of children in levels IV-V on all three measures was less than the criterion for a small effect. Minimal detectable change for each measure varied from 12.1 to 14.1, out of a total possible score of 100. Conclusion: Further research is recommended to determine responsiveness to change following intervention.

  10. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex.

    PubMed

    Kawaguchi, Yasuo; Kondo, Satoru

    2002-01-01

    It remains to be clarified how many classes of GABAergic nonpyramidal cells exist in the cortical circuit. We have divided GABA cells in the rat frontal cortex into 3 groups, based on their firing characteristics: fast-spiking (FS) cells, late-spiking (LS) cells, and non-FS cells. Expression of calcium-binding proteins and peptides could be shown in separate groups of GABA cells in layers II/III and V of the frontal cortex: (1) parvalbumin cells, (2) somatostatin cells, (3) calretinin and/or vasoactive intestinal polypeptide (VIP) cells [partially positive for cholecystokinin (CCK)] and (4) large CCK cells (almost negative for VIP/calretinin). Combining the physiological and chemical properties of morphologically diverse nonpyramidal cells allows division into several groups, including FS basket cells containing parvalbumin, non-FS somatostatin Martinotti cells with ascending axonal arbors, and non-FS large basket cells positive for CCK. These subtypes show characteristic spatial distributions of axon collaterals and the innervation tendency of postsynaptic elements. With synchronized activity induced by cortical excitatory or inhibitory circuits, firing patterns were also found to differ. Subtype-selective occurrence of electrical coupling, finding for potassium channel Kv3.1 proteins, and cholinergic and serotonergic modulation supports our tentative classification. To clarify the functional architecture in the frontal cortex, it is important to reveal the connectional characteristics of GABA cell subtypes and determine whether they are similar to those in other cortical regions.

  11. Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain.

    PubMed

    Réus, Gislaine Z; Stringari, Roberto B; Rezin, Gislaine T; Fraga, Daiane B; Daufenbach, Juliana F; Scaini, Giselli; Benedet, Joana; Rochi, Natália; Streck, Emílio L; Quevedo, João

    2012-04-01

    Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.

  12. [The surgical treatment of mandibular prognathism after the elimination of congenital clefts of the upper lip and palate].

    PubMed

    Kozlov, V A; Filatov, A V

    1994-01-01

    In 4.47% of observation in patients after liquidation of the cleft lip and the palate the lower prognathia is diagnosed. From 77 patients being operated for lower prognathia such kind of patients were 7. The subsequence of the treatment measures is the following: correction of the upper jaw on the basis of compactostetomy and it's subsequent widening with orthodontic devices. In case of impossibility of sufficient widening of the dental arch the removable dental prosthesis is made for application on the upper jaw with doubling dental row accounting achievement of the desired bite. At the second stage the osteotomy of the upper jaw brunch and sagittal removement of the central section back are carried out up to achievement of the neutral bite. In dependence on jaw sagittal removement degree operative treatment may be performed by the intravial (I degree) or extravial method (II-III progemy degrees). Quite satisfactory remote results are presented. The paper is illustrated by 4 figures. The list of literature is given.

  13. Paleocene-Eocene potential source rocks in the Avengco Basin, Tibet: Organic geochemical characteristics and their implication for the paleoenvironment

    NASA Astrophysics Data System (ADS)

    Han, Zhongpeng; Xu, Ming; Li, Yalin; Wei, Yushuai; Wang, Chengshan

    2014-10-01

    The Avengco Basin is located in the western part of the Tibetan Plateau and is similar to the Nima Basin in the central part of the plateau and the Lunpola Basin in the eastern part in terms of sedimentary characteristics and tectonic settings, which are well known to provide a good source rock potential. However, the organic geochemical characteristics of the Paleocene-Eocene potential source rocks in the Avengco Basin have been under debate. Thirty-four marl and mudstone outcrop samples of the Niubao Formation in the Avengco Basin were collected and subjected to the following analyses: total organic carbon (TOC), Rock-Eval pyrolysis, stable carbon isotopes of kerogen, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Here, we present the results indicating the organic matter of the upper Niubao Formation is mainly composed of Type II kerogen with a mixed source, which is dominated by algae. However, the lower Niubao Formation has the less oil-prone Type II-III kerogen, and the sources of the organic matter are mainly terrestrial plants with less plankton. In addition, the samples are thermally immature to marginally mature. The Niubao Formation was deposited in an anoxic-oxic environment which was brackish with an imperceptible stratified water column. The upper Niubao Formation has a medium to good hydrocarbon-generating potential. However, the lower Niubao Formation has a zero to poor hydrocarbon-generating potential.

  14. Potential role for clinical calibration to increase engagement with and application of home telemonitoring: a report from the HeartCycle programme

    PubMed Central

    Gastelurrutia, Paloma; Lupón, Josep; Domingo, Mar; Stut, Wim; Dovancescu, Silviu; Cleland, John; Frankenstein, Lutz

    2016-01-01

    Abstract Aims There is a need for alternative strategies that might avoid recurrent admissions in patients with heart failure. home telemonitoring (HTM) to monitor patient's symptoms from a distance may be useful. This study attempts to assess changes in HTM vital signs in response to daily life activities (variations in medication, salt intake, exercise, and stress) and to establish which variations affect weight, blood pressure, and heart rate. Methods and results We assessed 76 patients with heart failure (mean age 76 ± 10.8 years, 75% male, mainly in NYHA class II/III and from ischaemic aetiology cause). Patients were given a calendar of interventions scheduling activities approximately twice a week before measuring their vital signs. Eating salty food or a large meal were the activities that had a significant impact on weight gain (+0.3 kg; P < 0.001 and P = 0.006, respectively). Exercise and skipping a dose of medication other than diuretics increased heart rate (+3 bpm, P = 0.001 and almost +2 bpm, P = 0.016, respectively). Conclusions Our HTM system was able to detect small changes in vital signs related to these activities. Further studies should assess if providing such a schedule of activities might be useful for patient education and could improve long‐term adherence to recommended lifestyle changes. PMID:28217314

  15. Metallography and microstructure interpretation of some archaeological tin bronze vessels from Iran

    SciTech Connect

    Oudbashi, Omid; Davami, Parviz

    2014-11-15

    Archaeological excavations in western Iran have recently revealed a significant Luristan Bronzes collection from Sangtarashan archaeological site. The site and its bronze collection are dated to Iron Age II/III of western Iran (10th–7th century BC) according to archaeological research. Alloy composition, microstructure and manufacturing technique of some sheet metal vessels are determined to reveal metallurgical processes in western Iran in the first millennium BC. Experimental analyses were carried out using Scanning Electron Microscopy–Energy Dispersive X-ray Spectroscopy and Optical Microscopy/Metallography methods. The results allowed reconstructing the manufacturing process of bronze vessels in Luristan. It proved that the samples have been manufactured with a binary copper–tin alloy with a variable tin content that may relates to the application of an uncontrolled procedure to make bronze alloy (e.g. co-smelting or cementation). The presence of elongated copper sulphide inclusions showed probable use of copper sulphide ores for metal production and smelting. Based on metallographic studies, a cycle of cold working and annealing was used to shape the bronze vessels. - Highlights: • Sangtarashan vessels are made by variable Cu-Sn alloys with some impurities. • Various compositions occurred due to applying uncontrolled smelting methods. • The microstructure represents thermo-mechanical process to shape bronze vessels. • In one case, the annealing didn’t remove the eutectoid remaining from casting. • The characteristics of the bronzes are similar to other Iron Age Luristan Bronzes.

  16. Medical profession changes between religion, science, skill, ethics, law and economics.

    PubMed

    Angeletti, L R

    1997-01-01

    How has the medical profession changed during the centuries? How has the evolution of the profession been influenced by the balance of different issues, e.g. magic, religion, philosophy, science, technology, ethics, law and/or economics? One needs to examine many historical changes leading from the hierarchized medicine of Ancient Egypt to the Asklepiadic and Hippocratic medicine at the time of Plato, from the newly organized medicine of the Renaissance to the emerging social medicine of the XIX century, from the nosological medicine centered on the evaluation of the symptoms to the medicine which explores the human body through technologies. Furthermore, an overview from the past to the future should analyze the new doctor-patient relationship in a health system of managed care, between market and solidarity, between the efficientistic guidelines of the providers (hospitals, physicians, etc.) and an anthropocentric view of the rights of the citizen-customers. These problems are presented and discussed by many Authors in three issues of Medicina nei Secoli (II/III.1997-I, 1998) as an aid to understanding what it means to be a physician today, from the past to the future.

  17. AN-1792 (Elan).

    PubMed

    Thatte, U

    2001-05-01

    Elan is developing AN-1792 as a potential immunotherapy for Alzheimer's disease (AD). It is currently in phase I trials [350904]. Phase II/III trials, running in parallel in the US and UK, are expected to start by the end of 2001 [375061], [383226], [401966]. American Home Products (AHP) are collaborating with Elan on research and development of an immunotherapy directed towards the beta-amyloid peptide, including AN-1792 and other potential products [361702]. In September 2000, an agreement was established between Elan, AHP and Cambridge Antibody Technology (CAT), whereby CAT are investigating anti-beta-amyloid human antibodies [394844]. In July 2000, Merrill Lynch predicted a possible late-2001 entry into pivotal trials with a potential NDA filing in 2004 [375966]. The clinical program is expected to take approximately four years [339630]. In April 2001, ABN Amro Hoare Govett stated that, if data from the large phase II trial expected to start late in 2001 satisfied FDA requirements, then Elan might be able to file an NDA in 2003, with a potential launch in 2005 [407412].

  18. The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition.

    PubMed

    Monzote, Lianet; Lackova, Alexandra; Staniek, Katrin; Steinbauer, Silvia; Pichler, Gerald; Jäger, Walter; Gille, Lars

    2016-12-12

    Xanthohumol (Xan) is a natural constituent of human nutrition. Little is known about its actions on leishmanial parasites and their mitochondria as putative target. Therefore, we determined the antileishmanial activity of Xan and resveratrol (Res, as alternative compound with antileishmanial activity) with respect to mitochondria in Leishmania amazonensis promastigotes/amastigotes (LaP/LaA) in comparison with their activity in peritoneal macrophages from mouse (PMM) and macrophage cell line J774A.1 (J774). Mechanistic studies were conducted in Leishmania tarentolae promastigotes (LtP) and mitochondrial fractions isolated from LtP. Xan and Res demonstrated antileishmanial activity in LaA [half inhibitory concentration (IC50): Xan 7 µ m, Res 14 µ m]; while they had less influence on the viability of PMM (IC50: Xan 70 µ m, Res >438 µ m). In contrast to Res, Xan strongly inhibited oxygen consumption in Leishmania (LtP) but not in J774 cells. This was based on the inhibition of the mitochondrial electron transfer complex II/III by Xan, which was less pronounced with Res. Neither Xan nor Res increased mitochondrial superoxide release in LtP, while both decreased the mitochondrial membrane potential in LtP. Bioenergetic studies showed that LtP mitochondria have no spare respiratory capacity in contrast to mitochondria in J774 cells and can therefore much less adapt to stress by mitochondrial inhibitors, such as Xan. These data show that Xan may have antileishmanial activity, which is mediated by mitochondrial inhibition.

  19. Effects of genetic variants of CCR5 chemokine receptors on oral squamous cell carcinoma.

    PubMed

    Tanyel, C R; Cincin, Z B; Gokcen-Rohlig, B; Bektas-Kayhan, K; Unur, M; Cakmakoglu, B

    2013-11-18

    We aimed to evaluate the effect of genetic variants of the chemokine C-C motif receptor (CCR5) in the pathogenesis of oral squamous cell carcinoma (OSCC). A total of 127 patients diagnosed with OSCC and 104 healthy individuals were included in the study. The polymorphisms CCR5 59029 and CCR5-delta32 were assessed with the polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method from peripheral blood samples of both groups. There was a statistically significant difference between the control and patient groups for CCR5 59029 A/G genotypes (P < 0.01). Individuals carrying the CCR5 59029 G allele (GG +AG genotypes) had a 2.84-fold increased risk for OSCC (P < 0.0001), and the CCR5 59029 AA genotype frequency was higher in the control group than in the patient group (P < 0.0001). The CCR5-delta 32 genotype frequencies did not differ significantly between controls and cases (P > 0.05). CCR5 59029 GG and CCR5-delta32 DD + ID genotype frequencies were significantly increased in Grade II-III OSCC patients compared with Grade I-II OSCC patients. In conclusion, these results suggested that the G allele of the CCR5 59029 polymorphism might be a risk factor due to the loss of receptor function that might cause increased inflammation leading to the development of OSCC.

  20. Larval stages of the deep-sea lobster Polycheles typhlops (Decapoda, Polychelida) identified by DNA analysis: morphology, systematic, distribution and ecology

    NASA Astrophysics Data System (ADS)

    Torres, Asvin P.; Palero, Ferran; Dos Santos, Antonina; Abelló, Pere; Blanco, Edurne; Boné, Alexandra; Guerao, Guillermo

    2014-09-01

    A total of 25 specimens of Eryoneicus larvae were collected near the Balearic Archipelago (Western Mediterranean Sea) in 2009 and 2010. Detailed morphological examination indicated that the smallest individual corresponded with the first zoea (ZI) stage of Polycheles typhlops hatched from a berried female by Guerao and Abelló (J Nat Hist 30(8):1179-1184, 1996). Only two species of deep-sea polychelid lobster, namely P. typhlops and Stereomastis sculpta, are known to occur in the Mediterranean. Genetic distance comparisons and phylogenetic analysis of the mitochondrial 16S rDNA and Cox I genes of this early larva together with adults from several Polycheles and Stereomastis species allowed us to assign it to P. typhlops. This is the first wild-caught larval stage of a polychelid lobster being identified using molecular techniques. The remaining specimens were attributed to zoeal stages II-III and decapodid stage based on morphological comparison. The arrangement of spines along the anterior part of the middorsal line (R, 1, 1, 1, 2, C1), characteristic of the former species E. puritanii, discriminates these larvae from other Eryoneicus found in the Mediterranean. The clear presence of epipods on the third maxilliped and pereiopods of the decapodid stage gives further support to the identification of E. puritanii as the larval stages of P. typhlops. Additionally, information on the ecology of these larvae, their abundances during different seasons, as well as their bathymetric distribution is reported.

  1. Spatial resolution requirements for urban land cover mapping from space

    NASA Technical Reports Server (NTRS)

    Todd, William J.; Wrigley, Robert C.

    1986-01-01

    Very low resolution (VLR) satellite data (Advanced Very High Resolution Radiometer, DMSP Operational Linescan System), low resolution (LR) data (Landsat MSS), medium resolution (MR) data (Landsat TM), and high resolution (HR) satellite data (Spot HRV, Large Format Camera) were evaluated and compared for interpretability at differing spatial resolutions. VLR data (500 m - 1.0 km) is useful for Level 1 (urban/rural distinction) mapping at 1:1,000,000 scale. Feature tone/color is utilized to distinguish generalized urban land cover using LR data (80 m) for 1:250,000 scale mapping. Advancing to MR data (30 m) and 1:100,000 scale mapping, confidence in land cover mapping is greatly increased, owing to the element of texture/pattern which is now evident in the imagery. Shape and shadow contribute to detailed Level II/III urban land use mapping possible if the interpreter can use HR (10-15 m) satellite data; mapping scales can be 1:25,000 - 1:50,000.

  2. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed

    Kocer, Bilge; Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia.

  3. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed Central

    Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia. PMID:27493964

  4. Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat.

    PubMed

    Ishida, Akimasa; Misumi, Sachiyo; Ueda, Yoshitomo; Shimizu, Yuko; Cha-Gyun, Jung; Tamakoshi, Keigo; Ishida, Kazuto; Hida, Hideki

    2015-05-01

    Constraint-induced movement therapy (CIMT) promotes functional recovery of impaired forelimbs after hemiplegic strokes, including intracerebral hemorrhage (ICH). We used a rat model of subcortical hemorrhage to compare the effects of delivering early or late CIMT after ICH. The rat model was made by injecting collagenase into the globus pallidus near the internal capsule, and then forcing rats to use the affected forelimb for 7 days starting either 1 day (early CIMT) or 17 days (late CIMT) after the lesion. Recovery of forelimb function in the skilled reaching test and the ladder stepping test was found after early-CIMT, while no significant recovery was shown after late CIMT or in the non-CIMT controls. Early CIMT was associated with greater numbers of ΔFosB-positive cells in the ipsi-lesional sensorimotor cortex layers II-III and V. Additionally, we found expression of the growth-related genes brain-derived neurotrophic factor (BDNF) and growth-related protein 43 (GAP-43), and abundant dendritic arborization of pyramidal neurons in the sensorimotor area. Similar results were not detected in the contra-lesional cortex. In contrast to early CIMT, late CIMT failed to induce any changes in plasticity. We conclude that CIMT induces molecular and morphological plasticity in the ipsi-lesional sensorimotor cortex and facilitates better functional recovery when initiated immediately after hemorrhage.

  5. Early Prediction of the Response of Breast Tumors to Neoadjuvant Chemotherapy using Quantitative MRI and Machine Learning

    PubMed Central

    Mani, Subramani; Chen, Yukun; Arlinghaus, Lori R.; Li, Xia; Chakravarthy, A. Bapsi; Bhave, Sandeep R.; Welch, E. Brian; Levy, Mia A.; Yankeelov, Thomas E.

    2011-01-01

    The ability to predict early in the course of treatment the response of breast tumors to neoadjuvant chemotherapy can stratify patients based on response for patient-specific treatment strategies. Currently response to neoadjuvant chemotherapy is evaluated based on physical exam or breast imaging (mammogram, ultrasound or conventional breast MRI). There is a poor correlation among these measurements and with the actual tumor size when measured by the pathologist during definitive surgery. We tested the feasibility of using quantitative MRI as a tool for early prediction of tumor response. Between 2007 and 2010 twenty consecutive patients diagnosed with Stage II/III breast cancer and receiving neoadjuvant chemotherapy were enrolled on a prospective imaging study. Our study showed that quantitative MRI parameters along with routine clinical measures can predict responders from non-responders to neoadjuvant chemotherapy. The best predictive model had an accuracy of 0.9, a positive predictive value of 0.91 and an AUC of 0.96. PMID:22195145

  6. Diagnosing mucopolysaccharidosis IVA.

    PubMed

    Wood, Timothy C; Harvey, Katie; Beck, Michael; Burin, Maira Graeff; Chien, Yin-Hsiu; Church, Heather J; D'Almeida, Vânia; van Diggelen, Otto P; Fietz, Michael; Giugliani, Roberto; Harmatz, Paul; Hawley, Sara M; Hwu, Wuh-Liang; Ketteridge, David; Lukacs, Zoltan; Miller, Nicole; Pasquali, Marzia; Schenone, Andrea; Thompson, Jerry N; Tylee, Karen; Yu, Chunli; Hendriksz, Christian J

    2013-03-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.

  7. Acute Toxicity of Radiochemotherapy in Rectal Cancer Patients: A Risk Particularly for Carriers of the TGFB1 Pro25 variant

    SciTech Connect

    Schirmer, Markus Anton; Mergler, Caroline Patricia Nadine; Rave-Fraenk, Margret; Herrmann, Markus Karl; Hennies, Steffen; Gaedcke, Jochen; Conradi, Lena-Christin; Jo, Peter; Beissbarth, Tim; Hess, Clemens Friedrich; Becker, Heinz; Ghadimi, Michael; Brockmoeller, Juergen; Christiansen, Hans; Wolff, Hendrik Andreas

    2012-05-01

    Purpose: Transforming growth factor-beta1 is related to adverse events in radiochemotherapy. We investigated TGFB1 genetic variability in relation to quality of life-impairing acute organ toxicity (QAOT) of neoadjuvant radiochemotherapy under clinical trial conditions. Methods and Materials: Two independent patient cohorts (n = 88 and n = 75) diagnosed with International Union Against Cancer stage II/III rectal cancer received neoadjuvant radiation doses of 50.4 Gy combined with 5-fluorouracil-based chemotherapy. Toxicity was monitored according to Common Terminology Criteria for Adverse Events. QAOT was defined as a CTCAE grade {>=}2 for at least one case of enteritis, proctitis, cystitis, or dermatitis. Nine germline polymorphisms covering the common genetic diversity in the TGFB1 gene were genotyped. Results: In both cohorts, all patients carrying the TGFB1 Pro25 variant experienced QAOT (positive predictive value of 100%, adjusted p = 0.0006). In a multivariate logistic regression model, gender, age, body mass index, type of chemotherapy, or disease state had no significant impact on QAOT. Conclusion: The TGFB1 Pro25 variant could be a relevant marker for individual treatment stratification and carriers may benefit from adaptive clinical care or specific radiation techniques.

  8. Immortal Time Bias: A Frequently Unrecognized Threat to Validity in the Evaluation of Postoperative Radiotherapy

    SciTech Connect

    Park, Henry S.; Gross, Cary P.; Makarov, Danil V.; Yu, James B.

    2012-08-01

    Purpose: To evaluate the influence of immortal time bias on observational cohort studies of postoperative radiotherapy (PORT) and the effectiveness of sequential landmark analysis to account for this bias. Methods and Materials: First, we reviewed previous studies of the Surveillance, Epidemiology, and End Results (SEER) database to determine how frequently this bias was considered. Second, we used SEER to select three tumor types (glioblastoma multiforme, Stage IA-IVM0 gastric adenocarcinoma, and Stage II-III rectal carcinoma) for which prospective trials demonstrated an improvement in survival associated with PORT. For each tumor type, we calculated conditional survivals and adjusted hazard ratios of PORT vs. postoperative observation cohorts while restricting the sample at sequential monthly landmarks. Results: Sixty-two percent of previous SEER publications evaluating PORT failed to use a landmark analysis. As expected, delivery of PORT for all three tumor types was associated with improved survival, with the largest associated benefit favoring PORT when all patients were included regardless of survival. Preselecting a cohort with a longer minimum survival sequentially diminished the apparent benefit of PORT. Conclusions: Although the majority of previous SEER articles do not correct for it, immortal time bias leads to altered estimates of PORT effectiveness, which are very sensitive to landmark selection. We suggest the routine use of sequential landmark analysis to account for this bias.

  9. Methicillin-resistant Staphylococcus saprophyticus isolates carrying staphylococcal cassette chromosome mec have emerged in urogenital tract infections.

    PubMed

    Higashide, Masato; Kuroda, Makoto; Omura, Carlos Takashi Neves; Kumano, Miyuki; Ohkawa, Saburo; Ichimura, Sadahiro; Ohta, Toshiko

    2008-06-01

    Staphylococcus saprophyticus is a uropathogenic bacterium that causes acute uncomplicated urinary tract infections, particularly in female outpatients. We investigated the dissemination and antimicrobial susceptibilities of 101 S. saprophyticus isolates from the genitourinary tracts of patients in Japan. Eight of these isolates were mecA positive and showed beta-lactam resistance. Pulsed-field gel electrophoresis showed that only some isolates were isogenic, indicating that the mecA gene was apparently acquired independently by mecA-positive isolates through staphylococcal cassette chromosome mec (SCCmec). Type determination of SCCmec by multiplex PCR showed a nontypeable element in the eight mecA-positive isolates. Sequence analysis of the entire SCCmec element from a prototype S. saprophyticus strain revealed that it was nontypeable with the current SCCmec classification due to the novel composition of the class A mec gene complex (IS431-mecA-mecR1-mecI genes) and the ccrA1/ccrB3 gene complex. Intriguingly, the attachment sites of SCCmec are similar to those of type I SCCmec in S. aureus NCTC 10442. Furthermore, the genes around the mec gene complex are similar to those of type II/III SCCmec in S. aureus, while those around the ccr gene complex are similar to those of SCC15305RM found in S. saprophyticus ATCC 15305. In comparison with known SCCmec elements, this S. saprophyticus SCCmec is a novel type.

  10. Cyclodepsipeptides produced by actinomycetes inhibit cyclic-peptide-mediated quorum sensing in Gram-positive bacteria.

    PubMed

    Desouky, Said E; Shojima, Akane; Singh, Ravindra Pal; Matsufuji, Takahisa; Igarashi, Yasuhiro; Suzuki, Takashi; Yamagaki, Tohru; Okubo, Ken-Ichi; Ohtani, Kaori; Sonomoto, Kenji; Nakayama, Jiro

    2015-07-01

    Cyclic peptides are commonly used as quorum-sensing autoinducers in Gram-positive Firmicutes bacteria. Well-studied examples of such molecules are thiolactone and lactone, used to regulate the expression of a series of virulence genes in the agr system of Staphylococcus aureus and the fsr system of Enterococcus faecalis, respectively. Three cyclodepsipeptides WS9326A, WS9326B and cochinmicin II/III were identified as a result of screening actinomycetes culture extracts for activity against the agr/fsr system. These molecules are already known as receptor antagonists, the first two for tachykinin and the last one for endothelin. WS9326A also inhibited the transcription of pfoA regulated by the VirSR two-component system in Clostridium perfringens. Receptor-binding assays using a fluorescence-labeled autoinducer (FITC-GBAP) showed that WS9326A and WS9326B act as receptor antagonists in this system. In addition, an ex vivo assay showed that WS9326B substantially attenuated the toxicity of S. aureus for human corneal epithelial cells. These results suggest that these three natural cyclodepsipeptides have therapeutic potential for targeting the cyclic peptide-mediated quorum sensing of Gram-positive pathogens.

  11. Management of renal angiomyolipoma in patients with tuberous sclerosis complex.

    PubMed

    Simmons, J L; Hussain, S A; Riley, P; Wallace, D M A

    2003-01-01

    Renal angiomyolipomas are common in patients with tuberous sclerosis complex (TSC), and the risk of severe haemorrhage from these angiomyolipomas can become substantial. This case illustrates a potentially life-threatening condition due to the development of a large aneurysm within an angiomyolipoma, which was discovered within 14 months of her screening renal ultrasound scan. Renal arterial embolisation and renal sparing surgery resulted in good recovery. Clear guidelines for the screening, surveillance, and treatment of angiomyolipomas in patients with TSC are required. This includes the appropriate frequency of surveillance for patients in different age groups and at different stages of angiomyolipoma development, based on a growing knowledge of the natural history of this condition, since growth of renal angiomyolipomas can be rapid and asymptomatic. Computed tomography or magnetic resonance imaging may be required to demonstrate complications in large lesions, as three ultrasound examinations in this patient failed to detect the large aneurysm which had developed. Angiogenesis inhibitors could potentially play a role in preventing the development of angiomyolipomas, which could improve the prognosis for patients with TSC and therefore warrants investigation through phase II/III clinical trials.

  12. Sensory deprivation unmasks a PKA-dependent synaptic plasticity mechanism that operates in parallel with CaMKII.

    PubMed

    Hardingham, Neil; Wright, Nick; Dachtler, James; Fox, Kevin

    2008-12-10

    Calcium/calmodulin kinase II (CaMKII) is required for LTP and experience-dependent potentiation in the barrel cortex. Here, we find that whisker deprivation increases LTP in the layer IV to II/III pathway and that PKA antagonists block the additional LTP. No LTP was seen in undeprived CaMKII-T286A mice, but whisker deprivation again unmasked PKA-sensitive LTP. Infusion of a PKA agonist potentiated EPSPs in deprived wild-types and deprived CaMKII-T286A point mutants but not in undeprived animals of either genotype. The PKA-dependent potentiation mechanism was not present in GluR1 knockouts. Infusion of a PKA antagonist caused depression of EPSPs in undeprived but not deprived cortex. LTD was occluded by whisker deprivation and blocked by PKA manipulation, but not blocked by cannabinoid antagonists. NMDA receptor currents were unaffected by sensory deprivation. These results suggest that sensory deprivation causes synaptic depression by reversing a PKA-dependent process that may act via GluR1.

  13. Palynology, palynofacies and petroleum potential of the Upper Cretaceous-Eocene Matulla, Brown Limestone and Thebes formations, Belayim oilfields, central Gulf of Suez, Egypt

    NASA Astrophysics Data System (ADS)

    El Diasty, W. Sh.; El Beialy, S. Y.; Abo Ghonaim, A. A.; Mostafa, A. R.; El Atfy, H.

    2014-07-01

    Palynological, palynofacies and organic geochemical results of 46 samples retrieved from the Upper Cretaceous - Eocene Matulla, Brown Limestone and Thebes formations, Belayim oilfields, central Gulf of Suez, Egypt are presented. The two latter formations are not dated palynologically as their lithology is not promising for palynological yield. However the Matulla Formation is dated as Turonian-Santonian age, based on the combined evidence of pollen and dinocysts. Palynofacies analysis carried out under both transmitted and fluorescent microscopy indicated that both the Thebes and Brown Limestone formations are deposited under a distal suboxic-anoxic environment. On the other hand, the Turonian-Santonian Matulla Formation supported the existence of a marginal marine deposition under dysoxic-anoxic basin to proximal suboxic-anoxic shelf environments. Rock-Eval pyrolysis and TOC results indicated that most of the studied formations are thermally immature to marginally mature and have a good petroleum potential. They are organically-rich in both oil- and gas-prone kerogen Type-II and II/III, deposited under marine reducing conditions favorable for hydrocarbon generation and expulsion.

  14. High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer.

    PubMed

    Oue, Naohide; Anami, Katsuhiro; Schetter, Aaron J; Moehler, Markus; Okayama, Hirokazu; Khan, Mohammed A; Bowman, Elise D; Mueller, Annett; Schad, Arno; Shimomura, Manabu; Hinoi, Takao; Aoyagi, Kazuhiko; Sasaki, Hiroki; Okajima, Masazumi; Ohdan, Hideki; Galle, Peter R; Yasui, Wataru; Harris, Curtis C

    2014-04-15

    Colon cancer (CC) is a leading cause of cancer mortality. Novel biomarkers are needed to identify CC patients at high risk of recurrence and those who may benefit from therapeutic intervention. The aim of this study is to investigate if miR-21 expression from RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue sections is associated with prognosis and therapeutic outcome for patients with CC. The expression of miR-21 was measured by quantitative reverse transcriptase-polymerase chain reaction in a Japanese cohort (stage I-IV, n = 156) and a German cohort (stage II, n = 145). High miR-21 expression in tumors was associated with poor survival in both the stage II/III Japanese (p = 0.0008) and stage II German (p = 0.047) cohorts. These associations were independent of other clinical covariates in multivariable models. Receipt of adjuvant chemotherapy was not beneficial in patients with high miR-21 in either cohort. In the Japanese cohort, high miR-21 expression was significantly associated with poor therapeutic outcome (p = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21 (p = 0.001). These results suggest that miR-21 is a promising biomarker to identify patients with poor prognosis and can be accurately measured in FFPE tissues. The expression of miR-21 may also identify patients who will benefit from adjuvant chemotherapy.

  15. MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge.

    PubMed

    Roulois, David; Grégoire, Marc; Fonteneau, Jean-François

    2013-01-01

    MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.

  16. Perceived weight discrimination and chronic biochemical stress: A population‐based study using cortisol in scalp hair

    PubMed Central

    Kirschbaum, Clemens; Steptoe, Andrew

    2016-01-01

    Objective There is increasing evidence for weight‐based discrimination against persons with obesity. This study aimed to examine the physiological impact of perceived weight discrimination on cortisol in hair, an indicator of chronic stress exposure. Methods Data were from 563 nonsmoking individuals with obesity (body mass index, BMI ≥30 kg/m2) participating in the English Longitudinal Study of Ageing. Experiences of discrimination were reported via questionnaire, and hair cortisol concentrations were determined from the scalp‐nearest 2‐cm hair segment. Height and weight were objectively measured. ANCOVAs tested associations between perceived weight discrimination and hair cortisol concentration overall and by degree of obesity. All analyses were adjusted for age, sex, ethnicity, socioeconomic status, and BMI. Results Mean hair cortisol concentrations were 33% higher in those who had experienced weight discrimination than those who had not (mean log pg/mg 1.241 vs. 0.933, F = 12.01, P = 0.001). The association between weight discrimination and hair cortisol was particularly pronounced in individuals with severe (class II/III) obesity (1.402 vs. 0.972, F = 11.58, P = 0.001). Conclusions Weight discrimination is associated with the experience of stress at a biological level. Chronic exposure to elevated levels of cortisol may play a role in generating a vicious circle of weight gain and discrimination and contribute to obesity‐associated health conditions. PMID:27740706

  17. Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense.

    PubMed

    Fetoni, Anna Rita; De Bartolo, Paola; Eramo, Sara Letizia Maria; Rolesi, Rolando; Paciello, Fabiola; Bergamini, Christian; Fato, Romana; Paludetti, Gaetano; Petrosini, Laura; Troiani, Diana

    2013-02-27

    This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

  18. Adaptive designs undertaken in clinical research: a review of registered clinical trials.

    PubMed

    Hatfield, Isabella; Allison, Annabel; Flight, Laura; Julious, Steven A; Dimairo, Munyaradzi

    2016-03-19

    Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term 'adaptive design' should be included in the trial title or at least in the brief summary or design sections.

  19. The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy

    PubMed Central

    Zhao, Tingting; Xu, Zhi; Gu, Dongying; Wu, Peng; Huo, Xinying; Wei, Xiaowei; Tang, Yongfei; Gong, Weida; He, Ming-Liang; Chen, Jinfei

    2016-01-01

    5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log-rank tests and Kaplan–Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5′-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3′-UTR DD + DI and TS 5′-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5′-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU. PMID:27456431

  20. Effect of hindlimb unloading on stereological parameters of the motor cortex and hippocampus in male rats.

    PubMed

    Salehi, Mohammad Saied; Mirzaii-Dizgah, Iraj; Vasaghi-Gharamaleki, Behnoosh; Zamiri, Mohammad Javad

    2016-11-09

    Hindlimb unloading (HU) can cause motion and cognition dysfunction, although its cellular and molecular mechanisms are not well understood. The aim of the present study was to determine the stereological parameters of the brain areas involved in motion (motor cortex) and spatial learning - memory (hippocampus) under an HU condition. Sixteen adult male rats, kept under a 12 : 12 h light-dark cycle, were divided into two groups of freely moving (n=8) and HU (n=8) rats. The volume of motor cortex and hippocampus, the numerical cell density of neurons in layers I, II-III, V, and VI of the motor cortex, the entire motor cortex as well as the primary motor cortex, and the numerical density of the CA1, CA3, and dentate gyrus subregions of the hippocampus were estimated. No significant differences were observed in the evaluated parameters. Our results thus indicated that motor cortical and hippocampal atrophy and cell loss may not necessarily be involved in the motion and spatial learning memory impairment in the rat.

  1. Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil.

    PubMed

    Chrusciak-Talhari, Anette; Dietze, Reynaldo; Chrusciak Talhari, Carolina; da Silva, Roberto Moreira; Gadelha Yamashita, Ellen Priscila; de Oliveira Penna, Gerson; Lima Machado, Paulo Roberto; Talhari, Sinésio

    2011-02-01

    Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony.

  2. New categories designated as healthcare-associated and community-associated methicillin-resistant Staphylococcus pseudintermedius in dogs.

    PubMed

    Kasai, Tomoko; Saegusa, Sanae; Shirai, Mitsuyuki; Murakami, Masaru; Kato, Yukio

    2016-08-01

    The incidence of MRSP has been increasing, and treatment options in veterinary medicine are limited. Few previous studies of MRSP have described the relationships between the genotypes, phenotypes, and clinical backgrounds of the isolates. To gain insight into the associations between the microbiological and clinical characteristics of MRSP, we analyzed 282 Staphylococcus pseudintermedius isolates from dogs. A total of 195 (69.1%) strains were identified as mecA-positive MRSP and were classified into mainly two genotypes: SCCmec types III (II-III) (52.8%) and V (37.4%). SCCmec type III MRSP strains were significantly correlated with hospital admission and antimicrobial therapy of the dogs, and exhibited a homogeneous genotype similar to sequence type 71-MRSP, which is a globally endemic clone in dogs. In contrast, SCCmec type V MRSP strains were not highly correlated with hospital admission and antimicrobial therapy and exhibited genotypic and phenotypic heterogeneity. Properties of MRSP strains SCCmec types III and V were similar to those of HA- and CA-MRSA, respectively. Therefore, we designated these isolates carrying SCCmec types III and V as HA-MRSP and CA-MRSP, respectively. Discrimination between HA- and CA-MRSP by oxacillin MIC will provide useful information for treatment and infection control measures for canine MRSP infections.

  3. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

    PubMed Central

    Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio

    2016-01-01

    The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978

  4. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy.

    PubMed Central

    Ogasahara, S; Engel, A G; Frens, D; Mack, D

    1989-01-01

    The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy. The propositus, a 14-year-old female, and her 12-year-old sister had suffered from progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. In the propositus, the state 3 respiratory rate of muscle mitochondria with NADH-linked substrates and with succinate was markedly reduced. The levels of cytochromes a + a3, b, and c + c1 were normal. The activities of complexes I, II, III, and IV of the electron transport chain were normal or increased. By contrast, the activities of complex I-III and of complex II-III, both of which need coenzyme Q10 (CoQ10), were abnormally low. On direct measurement, the mitochondrial CoQ10 content was 3.7% of the mean value observed in 10 controls. Serum and cultured fibroblasts of the propositus had normal CoQ10 contents. In the younger sister, the respiratory activities and CoQ10 level of muscle mitochondria were similar to those observed in the propositus. The findings establish CoQ10 deficiency as a cause of a familial mitochondrial cytopathy and suggest that the disease results from a tissue-specific defect of CoQ10 biosynthesis. PMID:2928337

  5. Current Status and Future Prospects for Esophageal Cancer Treatment

    PubMed Central

    Kuwano, Hiroyuki

    2016-01-01

    The local control effect of esophagectomy with three-field lymph node dissection (3FLD) is reaching its limit pending technical advancement. Minimally invasive esophagectomy (MIE) by thoracotomy is slowly gaining acceptance due to advantages in short-term outcomes. Although the evidence is slowly increasing, MIE is still controversial. Also, the results of treatment by surgery alone are limiting, and multimodality therapy, which includes surgical and non-surgical treatment options including chemotherapy, radiotherapy, and endoscopic treatment, has become the mainstream therapy. Esophagectomy after neoadjuvant chemotherapy (NAC) is the standard treatment for clinical stages II/III (except for T4) esophageal cancer, whereas chemoradiotherapy (CRT) is regarded as the standard treatment for patients who wish to preserve their esophagus, those who refuse surgery, and those with inoperable disease. CRT is also usually selected for clinical stage IV esophageal cancer. On the other hand, with the spread of CRT, salvage esophagectomy has traditionally been recognized as a feasible option; however, many clinicians oppose the use of surgery due to the associated unfavorable morbidity and mortality profile. In the future, the improvement of each treatment result and the establishment of individual strategies are important although esophageal cancer has many treatment options. PMID:28003586

  6. Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients

    PubMed Central

    Mojarad, Ehsan Nazemalhosseini; Kashfi, Seyed Mohammad Hossein; Mirtalebi, Hanieh; Taleghani, Mohammad Yaghoob; Azimzadeh, Pedram; Savabkar, Sanaz; Pourhoseingholi, Mohammad Amin; Jalaeikhoo, Hasan; Asadzadeh Aghdaei, Hamid; Kuppen, Peter J. K.; Zali, Mohammad Reza

    2016-01-01

    The influence of microsatellite instability (MSI) on the prognosis of colorectal cancer (CRC) requires more investigation. We assessed the role of MSI status in survival of individuals diagnosed with primary colorectal cancer. In this retrospective cross-sectional study the MSI status was determined in 158 formalin-fixed paraffin-embedded tumors and their matched normal tissues from patients who underwent curative surgery. Cox proportional hazard modeling was performed to assess the clinical prognostic significance. In this study we found that MSI-H tumors were predominantly located in the colon versus rectum (p = 0.03), associated with poorer differentiation (p = 0.003) and TNM stage II/III of tumors (p = 0.02). In CRC patients with stage II, MSI-L cases showed significantly poorer survival compared with patients who had MSI-H or MSS tumors (p = 0.04). This study indicates that MSI-L tumors correlate with poorer clinical outcome in patients with stage II tumors (p = 0.04) or in tumors located in the colon (p = 0.02). MSI-L characterizes a distinct subgroup of CRC patients who have a poorer outcome. This study suggests that MSI status in CRC, as a clinical prognostic marker, is dependent on other factors, such as tumor stage and location. PMID:27429617

  7. Body Shape, Adiposity Index, and Mortality in Postmenopausal Women: Findings from the Women’s Health Initiative

    PubMed Central

    Thomson, Cynthia A.; Garcia, David O.; Wertheim, Betsy C.; Hingle, Melanie D.; Bea, Jennifer W.; Zaslavsky, Oleg; Caire-Juvera, Graciela; Rohan, Thomas; Vitolins, Mara Z.; Thompson, Patricia A.; Lewis, Cora E.

    2016-01-01

    Objective Studies evaluating the relationship between body mass index (BMI) and mortality demonstrate a U-shaped association. To expand, this study evaluated the relationship between adiposity indices, a body shape index (ABSI) and body adiposity index (BAI), and mortality in 77,505 postmenopausal women. Methods A prospective cohort analysis was conducted in the Women’s Health Initiative to ascertain the independent relationships between adiposity indices and mortality in order to inform on the clinical usefulness of alternate measures of mortality risk. ABSI (waist circumference (cm)/[BMI2/3 × height (cm)1/2]), BAI (hip circumference (cm)/[height (m)1.5] − 18), weight, BMI, and waist circumference (WC) were evaluated in relation to mortality risk using adjusted Cox proportional hazards regression models. Results ABSI showed a linear association with mortality (HR, 1.37; 95% CI, 1.28–1.47 for quintile 5 vs. 1) while BMI and BAI had U-shaped relationships with HR of 1.30; 95% CI, 1.20–1.40 for obesity II/III BMI and 1.06, 95% CI, 0.99–1.13 for BAI. Higher WC (HR, 1.21; 95% CI, 1.13–1.29 for quintile 5 vs. 1) showed relationships similar to BMI. Conclusions ABSI appears to be a clinically useful measure for estimating mortality risk, perhaps more so than BAI and BMI in postmenopausal women. PMID:26991923

  8. Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease.

    PubMed

    Alfadhel, Majid; Nashabat, Marwan; Abu Ali, Qais; Hundallah, Khalid

    2017-01-01

    Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications.

  9. Study of the rare decays {B}_{s,d}^{* } \\rightarrow {\\mu }^{+}{\\mu }^{-}

    NASA Astrophysics Data System (ADS)

    Sahoo, Suchismita; Mohanta, Rukmani

    2017-03-01

    We investigate the effect of scalar leptoquarks and family non-universal {Z}\\prime bosons on the rare leptonic decays of {B}s,d* mesons, mediated by the flavour-changing neutral-current transitions b\\to (d,s){l}+{l}-. They are sensitive to a variety of new physics operators as opposed to the {B}s,d leptonic modes and, hence, can provide an ideal testing ground to look for new physics beyond the Standard Model (SM). We work out the constraint on new physics parameter space using the measured branching ratios of {B}d,s\\to {μ }+{μ }- processes and the {B}q-{\\bar{B}}q mixing data. Using the constrained parameters we estimate the branching ratios of {B}d,s\\to {μ }+{μ }- ({e}+{e}-) processes. We find that the branching ratios are reasonably enhanced from their corresponding SM values in the X(3,2,1/6) leptoquark model and are expected to be within the reach of Run II/III of Large Hadron Collider experiments.

  10. Pegylated liposomal doxorubicin and immunomodulatory drug combinations in multiple myeloma: rationale and clinical experience.

    PubMed

    Chanan-Khan, Asher Alban; Lee, Kelvin

    2007-04-01

    The availability of new agents for multiple myeloma (MM) provides an opportunity to further improve response rates through the development of new combination regimens. Such new agents include pegylated liposomal doxorubicin (PLD) and the immunomodulatory drugs thalidomide and lenalidomide, all of which have demonstrated efficacy and safety in the treatment of newly diagnosed and relapsed/refractory MM. Based on their complementary mechanisms of action and nonoverlapping toxicity profiles, PLD and the immunomodulatory drugs might provide incremental benefits when used in combined treatment regimens. Thus, they have been evaluated in clinical studies that combine PLD/vincristine/dexamethasone and thalidomide (DVd-T) or PLD/vincristine/dexamethasone and lenalidomide (DVd-R) as well as in a study combining bortezomib with PLD and thalidomide. Results of all these studies have included high overall response rates, with improved rates of complete/near complete response compared with similar regimens that do not include chemotherapy (ie, immunomodulatory drugs plus dexamethasone). This article provides the clinical rationale for the use of PLD in combination with immunomodulatory drugs to treat patients with MM and summarizes the clinical experience with these combinations to date. Notably, the early phase I/II study results have been sufficiently encouraging to warrant further investigation in additional large-scale, phase II/III studies. Future clinical trials should focus on determining the optimal dose and schedule for each of these agents when used in combination and whether the addition of other new agents provides an additional response benefit.

  11. Prophylactic treatment with Bacopa monnieri leaf powder mitigates paraquat-induced oxidative perturbations and lethality in Drosophila melanogaster.

    PubMed

    Hosamani, Ravikumar; Muralidhara

    2010-04-01

    Environmental exposure to the oxidant-producing herbicide, paraquat (PQ) (1,1'-dimethyl-4,4'-bipyridinium dichloride) has long been implicated as a risk factor in Parkinson's disease (PD). PQ-induced oxidative stress has been exploited as a model to screen putative neuroprotective compounds employing Drosophila. In the present study, we investigated the prophylactic efficacy of Bacopa monnieri (BM) against PQ-induced oxidative stress, mitochondrial dysfunctions and lethality. Exposure of adult male flies (Oregon K) to PQ alone (40 mM in 5% sucrose) resulted in 50% mortality at 48 h. Prophylaxis (7 days) with BM extract (0.1%) offered significant protection (40%) against PQ-induced mortality. Further, oxidative impairments and mitochondrial dysfunctions were monitored among Drosophila exposed to PQ (20, 40 mM) for 24 h. Significant induction of oxidative stress was observed in terms of enhanced malondialdehyde and hydroperoxide levels, and elevated activities of antioxidant enzymes (catalase and SOD). Mitochondrial dysfunctions included of significant reduction in the activities of succinate dehydrogenase (23%), complex I-III (26%), and complex II-III (30%) enzymes. Interestingly, prophylaxis with BM extract prevented the oxidative stress induction by PQ and restored the activity of ETC complexes, suggesting clearly its specific effect on the mitochondria. While the precise mechanism of action of BM needs further investigations, it may be related to its ability to enhance antioxidant defences and thus mitigate PQ-induced oxidative stress in Drosophila.

  12. Characterization of the ionization degree evolution of the PF-400J plasma sheath by means of time resolved optical spectroscopy

    NASA Astrophysics Data System (ADS)

    Avaria, G.; Cuadrado, O.; Moreno, J.; Pavez, C.; Soto, L.

    2016-05-01

    Spectral measurements in the visible range of the plasma sheath ionization degree evolution on the plasma focus device PF-400J are presented. The measurements were done with temporal and spatial resolution in a plasma focus device of low stored energy: PF-400J (176-539 J, 880 nF, 20-35 kV, quarter period ∼ 300ns) [1]. An ICCD was attached to a 0.5 m focal length visible spectrometer, which enabled the acquisition of time resolved spectrum with 20 ns integration time throughout the whole current pulse evolution. The spatial resolution was attained using a set of lenses which allowed the focusing of a small volume of the plasma sheath in different positions of the inter-electrode space. Discharges were carried out in mixtures of Hydrogen with gases in different proportions: 5% Neon, 5% Krypton and 2% Nitrogen. Discharges using Neon as an impurity showed no ionization of the gas, just a very low intensity emission of Ne I at times much larger than the maximum current. Nitrogen, on the other hand, showed a high ionization reaching N V (N 4+) at the end of the axial phase, with a distinctive evolution of the ionization degree as the plasma sheath moved towards the end of the electrodes. A mixed result was found when using Krypton, since the ionization degree only reached levels around Kr II/III, even though it has an ionization potential lower than Neon.

  13. Evaluation of the In Vivo and In Vitro Effects of Fructose on Respiratory Chain Complexes in Tissues of Young Rats

    PubMed Central

    Macongonde, Ernesto António; Vilela, Thais Ceresér; Scaini, Giselli; Gonçalves, Cinara Ludvig; Ferreira, Bruna Klippel; Costa, Naithan Ludian Fernandes; de Oliveira, Marcos Roberto; Avila, Silvio; Streck, Emilio Luiz; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda

    2015-01-01

    Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 μmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients. PMID:26770008

  14. Laminar and regional distribution of galanin binding sites in cat and monkey visual cortex determined by in vitro receptor autoradiography

    SciTech Connect

    Rosier, A.M.; Vandesande, F.; Orban, G.A. )

    1991-03-08

    The distribution of galanin (GAL) binding sites in the visual cortex of cat and monkey was determined by autoradiographic visualization of ({sup 125}I)-GAL binding to tissue sections. Binding conditions were optimized and, as a result, the binding was saturable and specific. In cat visual cortex, GAL binding sites were concentrated in layers I, IVc, V, and VI. Areas 17, 18, and 19 exhibited a similar distribution pattern. In monkey primary visual cortex, the highest density of GAL binding sites was observed in layers II/III, lower IVc, and upper V. Layers IVA and VI contained moderate numbers of GAL binding sites, while layer I and the remaining parts of layer IV displayed the lowest density. In monkey secondary visual cortex, GAL binding sites were mainly concentrated in layers V-VI. Layer IV exhibited a moderate density, while the supragranular layers contained the lowest proportion of GAL binding sites. In both cat and monkey, we found little difference between regions subserving central and those subserving peripheral vision. Similarities in the distribution of GAL and acetylcholine binding sites are discussed.

  15. Mechanical properties of organic matter in shales mapped at the nanometer scale

    NASA Astrophysics Data System (ADS)

    Eliyahu, M.; Emmanuel, S.; Day-Stirrat, R. J.; Macaulay, C.

    2014-12-01

    The mechanical properties of organic matter strongly influence the way in which shales deform and fracture. However, the response of organic matter to mechanical stresses is not well understood, representing a critical obstacle to assessing oil and gas production in shale formations. Little is known about the mechanical properties of organic matter in fine grained rocks primarily because it often occupies tiny nanometer-scale voids between the mineral grains which cannot be accessed using standard mechanical testing techniques. Here, we report on the use of a new atomic force microscopy technique (PeakForce QNM) to map the mechanical properties of organic and inorganic components at the nanometer scale. We find that the method can identify different phases such as pyrite, quartz, clays, and organic matter. Furthermore, within the organic component Young's modulus values ranged from 0 - 25 GPa; in 3 different samples - all of which come from thermally mature Type II/III source rocks in the dry gas window - a modal value of 15-16 GPa was measured, with additional peaks measured at ≤ 10 GPa. In addition, the maps suggest that some porous organic macerals possess a soft core surrounded by a harder outer shell 50 - 100 nm thick. Our results demonstrate that the method represents a powerful new petrographic tool with which to characterize the mechanical properties of organic-rich sedimentary rocks.

  16. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network

    PubMed Central

    Harris, Julie A.; Devidze, Nino; Verret, Laure; Ho, Kaitlyn; Halabisky, Brian; Thwin, Myo T.; Kim, Daniel; Hamto, Patricia; Lo, Iris; Yu, Gui-Qiu; Palop, Jorge J.; Masliah, Eliezer; Mucke, Lennart

    2011-01-01

    SUMMARY The entorhinal cortex (EC) is one of the earliest affected and most vulnerable brain regions in Alzheimer’s disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. We show selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC causes cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. Overexpression of APP/Aβ in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1, as well as epileptiform activity in parietal cortex. Soluble Aβ was observed in the dentate gyrus and Aβ deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aβ expression in EC neurons can cause transsynaptic deficits, which could initiate the cortical-hippocampal network dysfunction observed in mouse models and human patients with AD. PMID:21040845

  17. Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

    PubMed Central

    Harris, Julie A.; Koyama, Akihiko; Maeda, Sumihiro; Ho, Kaitlyn; Devidze, Nino; Dubal, Dena B.; Yu, Gui-Qiu; Masliah, Eliezer; Mucke, Lennart

    2012-01-01

    Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here. PMID:23029293

  18. Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset

    PubMed Central

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-01-01

    Similarities between a mitochondrial disorder (MID) and amyotrophic lateral sclerosis (ALS) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (MIMODS). However, with mild MIMODS, a MID may still be misinterpreted as ALS. We report a 48-year-old male who presented to the Neurological Hospital Rosenhügel, Vienna, Austria, in February 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. Additionally, he developed tetraspasticity and bulbar involvement. He had been diagnosed with ALS a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. However, a muscle biopsy revealed morphological features of a MID and a combined complex-II/III defect. Nerve conduction studies were performed over subsequent years until February 2011. This case demonstrates that MIDs may mimic ALS at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. A combined complex II/III defect may manifest with bulbar involvement. PMID:26909222

  19. Orthogonal micro-organization of orientation and spatial frequency in primate primary visual cortex

    PubMed Central

    Nauhaus, Ian; Nielsen, Kristina J.; Disney, Anita A.; Callaway, Edward M.

    2012-01-01

    Orientation and spatial frequency tuning are highly salient properties of neurons in primary visual cortex (V1). The combined organization of these particular tuning properties in the cortical space will strongly shape the V1 population response to different visual inputs, yet it is poorly understood. In this study, we used two-photon imaging in macaque monkey V1 to provide the first data demonstrating the 3D cell-by-cell layout of both spatial frequency and orientation tuning in large mammals. We first show that spatial frequency tuning is organized into highly structured maps that remain consistent across the depth of layer II/III, similar to orientation. Next, we show that orientation and spatial frequency maps are intimately related at the fine spatial scale observed with two-photon imaging. We find that not only do the map gradients have a striking tendency toward orthogonality, but they also co-vary negatively from cell-to-cell at the spatial scale of cortical columns. PMID:23143516

  20. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    PubMed Central

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs. PMID:27656206

  1. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis

    PubMed Central

    Wu, Jiaying; Hong, Dongsheng; Zhang, Xiangnan; Lu, Xiaoyang; Miao, Jing

    2017-01-01

    Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18–3.90%) for all-grade and 1.53% (95%CI: 1.15–2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types. PMID:28272463

  2. The Lasioseius phytoseioides species group (Acari: Blattisociidae): new characterisation, description of a new species, complementary notes on seven described species and a taxonomic key for the group.

    PubMed

    De Moraes, Gilberto J; Abo-Shnaf, Reham I A; Pérez-Madruga, Yanebis; Sánchez, Leocadia; Karmakar, Krishna; Ho, Chyi-Chen

    2015-06-26

    The Lasioseius phytoseioides species group was first characterised over 50 years ago. Two species of this group, Lasioseius chaudhrii (Wu & Wang) and Lasioseius parberlesei Bhattacharyya, have been considered potentially effective as biological control agents of pest mites of the family Tarsonemidae on rice (Oryza sativa L.) in Asia. A new characterisation of the species group is presented, taking into account a new species here described, Lasioseius piracicabensis Moraes & Pérez-Madruga n. sp., as well as other species mostly described since the first characterisation of the group. The main characteristics of the included species are the reduced number of dorsal idiosomal setae, including the absence of j1 and z1; antiaxial surface of fixed cheliceral digit with a subterminal pointed process; and males with broad lateral expansion of the peritrematic shield in the region between coxae II-III, bearing a pore and a lyrifissure. Complementary notes are presented for Lasioseius annandalei Bhattacharyya & Bhattacharyya, Lasioseius chaudhrii (Wu & Wang), Lasioseius parberlesei Bhattacharyya, L. phytoseioides Chant, Lasioseius punjabensis Bhattacharyya & Sanyal, Lasioseius terrestris Menon & Ghai and Lasioseius youcefi Athias-Henriot. New synonymies are proposed and possible misidentifications in the literature are discussed. A dichotomous key is presented to help the identification of the species of the group, and the distribution of the species is summarised.

  3. Alpha-1 adrenergic receptors gate rapid orientation-specific reduction in visual discrimination.

    PubMed

    Treviño, Mario; Frey, Sebastian; Köhr, Georg

    2012-11-01

    Prolonged imbalance in sensory experience leads to dramatic readjustments in cortical representation. Neuromodulatory systems play a critical role in habilitating experience-induced plasticity and regulate memory processes in vivo. Here, we show that a brief period of intense patterned visual stimulation combined with systemic activation of alpha-1 adrenergic neuromodulator receptors (α(1)-ARs) leads to a rapid, reversible, and NMDAR-dependent depression of AMPAR-mediated transmission from ascending inputs to layer II/III pyramidal cells in the visual cortex of young and adult mice. The magnitude of this form of α(1)-AR long-term depression (LTD), measured ex vivo with miniature EPSC recordings, is graded by the number of orientations used during visual experience. Moreover, behavioral tests of visual function following the induction of α(1)-AR LTD reveal that discrimination accuracy of sinusoidal drifting gratings is selectively reduced at high spatial frequencies in a reversible, orientation-specific, and NMDAR-dependent manner. Thus, α(1)-ARs enable rapid cortical synaptic depression which correlates with an orientation-specific decrease in visual discrimination. These findings contribute to our understanding of how adrenergic receptors interact with neuronal networks in response to changes in active sensory experience to produce adaptive behavior.

  4. PHP-HT (VitaResc Biotech).

    PubMed

    Baldwin, A; Wiley, E

    2001-04-01

    VitaResc (formerly Apex) is developing PHP-HT, pyridoxalated hemoglobin polyoxyethylene conjugate, for the potential treatment of nitric oxide-induced shock (characterized by hypotension), associated with various etiologies, initially in septic shock. A phase I safety study and an initial phase I/II patient trial for NO-induced shock have been completed, and VitaResc has enrolled patients in three of five planned cohorts in a continuation of these trials to include a protocol of continuous infusion and dose escalation [330680,349187,390918]. The results from the dose escalation trials are expected to provide the basis for a randomized, controlled phase II/III pivotal trial of PHP-HT [390918]. VitaResc has licensed PHP-HT exclusively from Ajinomoto for all indications, worldwide, except Japan [275263]. Ajinomoto originally developed the human derived and chemically modified hemoglobin preparation as a blood substitute, but no development has been reported by the company since 1997 [275277,303577]. The other potential indications of PHP-HT include shock associated with burns, pancreatitis, hemodialysis and cytokine therapies [275277]. VitaResc expects the annual market potential of PHP-HT to exceed 1 billion dollars [330680].

  5. Alvimopan: a peripherally acting mu-opioid receptor antagonist.

    PubMed

    Leslie, John B

    2007-09-01

    Postoperative ileus (POI), a transient cessation of coordinated bowel motility after surgery, is an important factor in extending the length of hospital stay. The etiology of POI is multifactorial, and related to both the surgical and anesthetic pathways chosen. Additionally, opioids used to manage non-cancer-related and cancer-related chronic pain may also decrease gastrointestinal (GI) motility resulting in opioid-induced bowel dysfunction (OBD). Postoperative ileus has been associated with prolonged hospital stay and readmission, and thus may increase the overall hospital costs per patient with POI. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated time to GI recovery and reduced postoperative hospital length of stay in phase III POI clinical trials and improved symptoms of OBD compared with placebo in phase II/III clinical trials. The U.S. Food and Drug Administration is currently evaluating alvimopan for the management of POI after bowel resection. Alvimopan may provide clinically meaningful benefits to patients and may lower the economic burden of POI to the healthcare system.

  6. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors.

    PubMed

    Pusceddu, Sara; de Braud, Filippo; Concas, Laura; Bregant, Cristina; Leuzzi, Livia; Formisano, Barbara; Buzzoni, Roberto

    2014-01-01

    Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

  7. Tri-State Synfuels Project Review: Volume 8. Commercial status of licensed process units. [Proposed Henderson, Kentucky coal to gasoline plant; licensed commercial processes

    SciTech Connect

    Not Available

    1982-06-01

    This document demonstrates the commercial status of the process units to be used in the Tri-State Synfuels Project at Henderson, Kentucky. The basic design philosophy as established in October, 1979, was to use the commercial SASOL II/III plants as a basis. This was changed in January 1982 to a plant configuration to produce gasoline via a methanol and methanol to gasoline process. To accomplish this change the Synthol, Oil workup and Chemical Workup Units were eliminated and replaced by Methanol Synthesis and Methanol to Gasoline Units. Certain other changes to optimize the Lurgi liquids processing eliminated the Tar Distillation and Naphtha Hydrotreater Units which were replaced by the Partial Oxidation Unit. The coals to be gasified are moderately caking which necessitates the installation of stirring mechanism in the Lurgi Dry Bottom gasifier. This work is in the demonstration phase. Process licenses either have been obtained or must be obtained for a number of processes to be used in the plant. The commercial nature of these processes is discussed in detail in the tabbed sections of this document. In many cases there is a list of commercial installations at which the licensed equipment is used.

  8. Detection of novel polymorphisms in the ckit gene of canine patients with lymphoma, melanoma, haemangiosarcoma, and osteosarcoma.

    PubMed

    Gramer, Irina; Kessler, Martin; Geyer, Joachim

    2016-06-01

    Tyrosine kinase inhibitors (TKIs) that specifically target cKIT represent a therapeutic approach for non-resectable canine mast cell tumours (MCTs) grade II/III. The therapeutic benefit of TKIs has been investigated in other tumours based on clinical response rates and identification of gain-of-function mutations. In the present study, cKIT expression in 14 dogs with osteosarcoma, melanoma, haemangiosarcoma, lymphoma, and fibrosarcoma was analysed. Tissue samples were used for cKIT sequencing to (I) detect the cKIT transcript and to (II) identify gain-of-function mutations. The cKIT transcript was detected in ten patients. Four novel amino acid substitutions and five silent polymorphisms were identified. Furthermore, an insertion mutation (GNSK) was discovered in the tissue, but not in the blood sample of one dog. CKIT expression was identified in a variety of canine tumours and, therefore, TKIs might have a broader therapeutic indication apart from treatment of MCTs. Further investigations will be necessary to localize the cKIT protein in the respective tumours and to evaluate the functional consequence of the cKIT variants identified in the present study.

  9. Irreversible deformation processes in PVC and its short glass fiber reinforced composites

    SciTech Connect

    Yuan, J.Y.

    1985-01-01

    The tensile mechanical behavior of PVC and its short glass fiber reinforced composites under superimposed hydrostatic pressure was studied up to 3 x 10/sup 8/ Pa. For rigid PVC, the brittle-to-ductile transition was observed at a pressure between 1 x 10/sup 7/ Pa and 2 x 10/sup 7/ Pa. This pressure-induced brittle-to-ductile transition was controlled by the competitive microdeformation processes of crazing and shear banding. Deformation in the post-yield region occurred by neck formation and subsequent drawing to produce chain orientation. A strong environmental stress-cracking effect was observed when PVC samples were exposed to the pressure-transmitting fluid, silicone oil. Three types of pressure dependent deformation processes was observed for the short glass fiber reinforced composites of PVC. Type I behavior shows debonding at the interface between fiber and matrix followed by brittle fracture of the matrix. Type II behavior, which was observed for the first time, exhibits a sharp stress drop due to debonding at the interface followed by matrix shear yielding. In Type III behavior, only upper shear yielding of matrix was observed. The transitional behavior from Type I and Type II was controlled by the pressure induced brittle to ductile transition of the matrix, while the Type II-III transition was strongly affected by debonding at the interface.

  10. A comparative study on the in vitro cytotoxic responses of two mammalian cell types to fullerenes, carbon nanotubes and iron oxide nanoparticles.

    PubMed

    Dönmez Güngüneş, Çiğdem; Şeker, Şükran; Elçin, Ayşe Eser; Elçin, Yaşar Murat

    2017-04-01

    The present study was designed to evaluate and compare the time- and dose-dependent cellular response of human periodontal ligament fibroblasts (hPDLFs), and mouse dermal fibroblasts (mDFs) to three different types of nanoparticles (NPs); fullerenes (C60), single walled carbon nanotubes (SWCNTs) and iron (II,III) oxide (Fe3O4) nanoparticles via in vitro toxicity methods, and impedance based biosensor system. NPs were characterized according to their morphology, structure, surface area, particle size distribution and zeta potential by using transmission electron microscopy, X-ray diffraction, Brunauer-Emmett-Teller, dynamic light scattering and zeta sizer analyses. The Mössbauer spectroscopy was used in order to magnetically characterize the Fe3O4 NPs. The hPDLFs and mDFs were exposed to different concentrations of the NPs (0.1, 1, 10, 50 and 100 μg/mL) for predetermined time intervals (6, 24 and 48 h) under controlled conditions. Subsequently, NP exposed cells were tested for viability, membrane leakage and generation of intracellular reactive oxygen species. Additional to in vitro cytotoxicity assays, the cellular responses to selected NPs were determined in real time using an impedance based biosensor system. Taken together, information obtained from all experiments suggests that toxicity of the selected NPs is cell type, concentration and time dependent.

  11. The impact of maxillary osteotomy on speech outcomes in cleft lip and palate: an evidence-based approach to evaluating the literature.

    PubMed

    Pereira, Valerie; Sell, Debbie; Tuomainen, Jyrki

    2013-01-01

    Objective : To undertake a critical and systematic review of the literature on the impact of maxillary advancement on speech outcomes in order to identify current best evidence. Design and Main Outcome Measures : The following databases were searched: PubMed, CINAHL, and The Cochrane Controlled Trials Register. In addition, reference lists were hand searched for additional articles. Using a predefined framework and set criteria, evidence was evaluated using the assignment of levels of evidence (at least Level III on the evidence hierarchy), calculation of post-hoc power (≥ 0.8), effect size (Cohen's d ≥ 0.5), and adaptation of the parameters as set out by The Cochrane Collaboration. Results : Of the 40 studies identified, the majority (68%) fell within Level III.ii, representing cohort-type studies and a fifth (20%) within Level IV, the weakest form of evidence. Power and effect size calculations were only possible in 9 studies for different speech outcomes, and only seven studies met the set criteria for best evidence. Accordingly, current best evidence for articulation exists only for a noncleft population, is conflicting for resonance and nasalance, and is mixed for velopharyngeal function depending on which instrumental measure is used. Conclusions : There is an obvious need for further prospective research in the field with strong speech methodology such as the undertaking of interrater and intrarater reliability, adequate follow-up, and sufficient sample sizes based on a priori power analyses. Methodologic issues are discussed and recommendations made.

  12. Avian magnetoreception: elaborate iron mineral containing dendrites in the upper beak seem to be a common feature of birds.

    PubMed

    Falkenberg, Gerald; Fleissner, Gerta; Schuchardt, Kirsten; Kuehbacher, Markus; Thalau, Peter; Mouritsen, Henrik; Heyers, Dominik; Wellenreuther, Gerd; Fleissner, Guenther

    2010-02-16

    The magnetic field sensors enabling birds to extract orientational information from the Earth's magnetic field have remained enigmatic. Our previously published results from homing pigeons have made us suggest that the iron containing sensory dendrites in the inner dermal lining of the upper beak are a candidate structure for such an avian magnetometer system. Here we show that similar structures occur in two species of migratory birds (garden warbler, Sylvia borin and European robin, Erithacus rubecula) and a non-migratory bird, the domestic chicken (Gallus gallus). In all these bird species, histological data have revealed dendrites of similar shape and size, all containing iron minerals within distinct subcellular compartments of nervous terminals of the median branch of the Nervus ophthalmicus. We also used microscopic X-ray absorption spectroscopy analyses to identify the involved iron minerals to be almost completely Fe III-oxides. Magnetite (Fe II/III) may also occur in these structures, but not as a major Fe constituent. Our data suggest that this complex dendritic system in the beak is a common feature of birds, and that it may form an essential sensory basis for the evolution of at least certain types of magnetic field guided behavior.

  13. [Pregnancy in a patient with mitochondrial disease].

    PubMed

    Racine, A-C; Blanchot, G; Le Vaillant, C; Boog, G

    2004-04-01

    We report a case of a pregnant woman with a mitochondrial disorder affecting the energy-generating pathway of oxidative phosphorylation which was suggested when the patient presented the progressive clinical phenotype of a proximal tubular renal insufficiency, a muscular weakness of extremities, a bilateral optic neuropathy and a brain magnetic resonance imaging suggesting diffuse leucoencephalopathy. Her diagnosis was made on the basis of abnormal mitochondria on a muscle biopsy and of spectrophotometric deficiencies of the complexes I, II+III and IV of the respiratory chain. No specific molecular mutation could be detected. Her pregnancy was complicated by a severe preeclampsia, an insulin requiring gestational diabetes and a worrying renal failure which precipitated the premature delivery by cesarean section at 30 weeks gestation. The clinical course of the female neonate weighing 1030 grams was uneventful. At two Years of age she showed no sign of mitochondrial disease. But the postpartum course of the mother was complicated by seizures and a terminal renal failure leading presently to dialysis, but requiring a kidney transplantation in the near future.

  14. Sensorimotor development in neonatal progesterone receptor knockout mice.

    PubMed

    Willing, Jari; Wagner, Christine K

    2014-01-01

    Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally-critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42-56; Lopez & Wagner [2009]: J Comp Neurol 512:124-139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2-3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration.

  15. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches.

  16. Human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for the prevention of cervical cancer and HPV-related diseases.

    PubMed

    Skinner, S Rachel; Apter, Dan; De Carvalho, Newton; Harper, Diane M; Konno, Ryo; Paavonen, Jorma; Romanowski, Barbara; Roteli-Martins, Cecilia; Burlet, Nansa; Mihalyi, Attila; Struyf, Frank

    2016-01-01

    Vaccines are available against human papillomavirus (HPV), the causal agent of cervical and other cancers. Efficacy data from the HPV-16/18 AS04-adjuvanted vaccine clinical trial program were reviewed. Six randomized, controlled phase II/III trials evaluating cervical endpoints enrolled women from diverse populations and geographical locations. The program analyzed extensively the cohorts most relevant from a public health perspective: the total vaccinated cohort (TVC), approximating a general population including those with existing or previous HPV infection, and TVC-naïve, approximating a population of young women before sexual debut. Results show that the vaccine reduces HPV-16/18 infection and associated cervical endpoints in women regardless of age, location, or sexual experience. It provides cross-protection against some non-vaccine oncogenic HPV types and types causing genital warts, and may be effective against vulvar, oral, and anal HPV infection. Early epidemiology data following its introduction suggest a decline in the prevalence of vaccine and some non-vaccine HPV types.

  17. [Combined spinal epidural anesthesia during endoprosthetic surgeries for bone tumors in old-age children].

    PubMed

    Matinian, N V; Saltanov, A I

    2005-01-01

    Thirty-five patients (ASA II-III) aged 12 to 17 years, diagnosed as having osteogenic sarcoma and Ewing's sarcoma localizing in the femur and tibia, were examined. Surgery was performed as sectoral resection of the affected bone along with knee joint endoprosthesis. Surgical intervention was made under combined spinal and epidural anesthesia (CSEA) with sedation, by using the methods for exact dosing of propofol (6-4 mg/kg x h). During intervention, a child's respiration remains is kept spontaneous with oxygen insufflation through a nasal catheter. CSEA was performed in two-segmental fashion. The epidural space was first catheterized. After administration of a test dose, 0.5% marcaine spinal was injected into dermatomas below the subarachnoidal space, depending on body weight (3.0-4.0 ml). Sensory blockade developed following 3-5 min and lasted 90-120 min, thereafter a local anesthetic (bupivacaine) or its mixture plus promedole was epidurally administered. ??Anesthesia was effective in all cases, motor blockade. During surgery, there was a moderate arterial hypotension that did not require the use of vasopressors. The acid-alkali balance suggested the adequacy of spontaneous respiration. The only significant complication we observed was atony of the bladder that requires its catheterization till the following day. An epidural catheter makes it possible to effect adequate postoperative analgesia.

  18. Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies.

    PubMed

    Allison, R R; Mang, T S; Wilson, B D

    1998-06-01

    Photodynamic therapy (PDT) is a modality whose concept is not new to dermatologists. PDT has gained regulatory approval in the United States for the treatment of esophageal and lung malignancies. The field has grown over the last decade, and now phase II/III clinical trials using second generation drugs for the treatment of nonmelanoma skin cancers, palliation of metastases to the skin, and Kaposi's sarcomas have been introduced. These new sensitizers tend to reduce the one side effect of PDT, namely persistent generalized cutaneous photosensitivity. PDT has shown efficacy in (1) patients who have failed conventional therapies, and for whom local treatment options are limited (2) patients in whom surgery would result in cosmetic disfigurement, and (3) patients prone to developing multiple lesions as in Gorlins syndrome. Dosimetry is based on well-understood treatment matrices that have optimized light delivery with known photosensitizer administrations. The advantages of PDT for cutaneous malignancies include the ability to treat numerous lesions in one setting, in a noninvasive manner without any apparent concern for the development of carcinogenicity.

  19. Antimicrobial resistance of Staphylococcus pseudintermedius isolates from healthy dogs and dogs affected with pyoderma in Japan.

    PubMed

    Onuma, Kenta; Tanabe, Taishi; Sato, Hisaaki

    2012-02-01

    Staphylococcus pseudintermedius strains were isolated from healthy dogs and dogs with pyoderma in 2000-2002 and 2009. All the isolates from dogs with pyoderma in 1999-2000 and from healthy dogs in 2000-2002 and 2009 were susceptible to cefalexin and/or other cephalosporins and oxacillin. However, 7.1-12.5 and 11.4% of S. pseudintermedius isolates from dogs with pyoderma in 2009 were resistant to cephalosporins and oxacillin, respectively. All S. pseudintermedius isolates from dogs with pyoderma in 1999-2000 and those from healthy dogs in 2000-2002 were susceptible to fluoroquinolones; however, 50% of the S. pseudintermedius strains isolated from dogs with pyoderma in 2009 and 30% of the S. pseudintermedius strains isolated from healthy dogs in 2009 were resistant to fluoroquinolones. Of the 21 oxacillin-resistant S. pseudintermedius (MRSP) isolates, 11 carried SCCmec type V and 10 carried hybrid SCCmec types II-III. Staphylococcus pseudintermedius strains that were resistant to only one of three fluoroquinolones had a mutation in the quinolone resistance determination region of grlA, whereas S. pseudintermedius strains that were resistant to two or more fluoroquinolones had mutations in the quinolone resistance determination regions of both grlA and gyrA.

  20. Sample size planning for phase II trials based on success probabilities for phase III.

    PubMed

    Götte, Heiko; Schüler, Armin; Kirchner, Marietta; Kieser, Meinhard

    2015-01-01

    In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time-to-event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no-go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no-go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be.

  1. Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury

    PubMed Central

    2009-01-01

    The anterior cingulate cortex (ACC) is important for cognitive and sensory functions including memory and chronic pain. Glutamatergic excitatory synaptic transmission undergo long-term potentiation in ACC pyramidal cells after peripheral injury. Less information is available for the possible long-term changes in neuronal action potentials or intrinsic properties. In the present study, we characterized cingulate pyramidal cells in the layer II/III of the ACC in adult mice. We then examined possible long-term changes in intrinsic properties of the ACC pyramidal cells after peripheral nerve injury. In the control mice, we found that there are three major types of pyramidal cells according to their action potential firing pattern: (i) regular spiking (RS) cells (24.7%), intrinsic bursting (IB) cells (30.9%), and intermediate (IM) cells (44.4%). In a state of neuropathic pain, the population distribution (RS: 21.3%; IB: 31.2%; IM: 47.5%) and the single action potential properties of these three groups were indistinguishable from those in control mice. However, for repetitive action potentials, IM cells from neuropathic pain animals showed higher initial firing frequency with no change for the properties of RS and IB neurons from neuropathic pain mice. The present results provide the first evidence that, in addition to synaptic potentiation reported previously, peripheral nerve injury produces long-term plastic changes in the action potentials of cingulate pyramidal neurons in a cell type-specific manner. PMID:20015370

  2. Nrdp1-mediated ErbB3 degradation inhibits glioma cell migration and invasion by reducing cytoplasmic localization of p27(Kip1).

    PubMed

    Shi, Hengliang; Gong, Hui; Cao, Kuan; Zou, Shenshan; Zhu, Bingxin; Bao, Hanmo; Wu, Yuxuan; Gao, Yong; Tang, Yuan; Yu, Rutong

    2015-09-01

    We previously reported that loss of Nrdp1 contributes to human glioma progression by reducing apoptosis. However, the role of Nrdp1 in glioma migration and invasion has not been investigated. Here, we report that ErbB3, a substrate of Nrdp1, is undetectable in normal brain tissues and grade II/III glioma tissues, but is abundant in a certain percentage of grade IV glioma tissues and is associated with the loss of Nrdp1. This suggests that Nrdp1 may be involved in glioma migration and invasion by regulating ErbB3. Thus, the role of Nrdp1/ErbB3 signaling in glioma cell migration and invasion was investigated using Nrdp1 loss- and gain-of-function. The results show that down-regulation of Nrdp1 by use of short hairpin RNA promoted glioma cell migration and invasion. In contrast, overexpression of Nrdp1 significantly inhibited glioma cell migration and invasion. Further investigation on molecular targets revealed that Nrdp1 decreased the level of ErbB3, which resulted in decreasing p-AKT thereby reducing cytoplasmic p27(Kip1). Taken together, these findings suggest that Nrdp1-mediated ErbB3 degradation suppresses glioma migration and invasion and that loss of Nrdp1 may amplify ErbB3 signaling to contribute to glioma migration and invasion. These findings suggest that Nrdp1 may be a target for glioma therapy.

  3. Series of Phase Transitions in Cesium Azide Under High Pressure Studied by in situ X-ray Diffraction

    SciTech Connect

    D Hou; F Zhang; C Ji; T Hannon; H Zhu; J Wu; Y Ma

    2011-12-31

    In situ x-ray diffraction measurements of cesium azide (CsN{sub 3}) were performed at high pressures of up to 55.4 GPa at room temperature. Three phase transitions were revealed as follows: tetragonal (I4/mcm, Phase II) {yields} monoclinic (C2/m, Phase III) {yields} monoclinic (P2{sub 1}/m or P2{sub 1}, Phase IV) {yields} triclinic (P1 or P1{sup -}, Phase V), at 0.5, 4.4, and 15.4 GPa, respectively. During the II-III phase transition, CsN{sub 3} keeps its layered structure and the azide anions rotate obviously. The compressibility of Phase II is dominated by the repulsions between azide anions. The deformation of unit cell is isotropic in Phases II and IV and anisotropic in Phase III. With increasing pressures, the monoclinic angle increases in Phase III and then becomes stable in Phase IV. The bulk moduli of Phases II, III, IV, and V are determined to be 18 {+-} 4, 20 {+-} 1, 27 {+-} 1 and 34 {+-} 1 GPa, respectively. The ionic character of alkali azides is found to play a key role in their pressure-induced phase transitions.

  4. A Novel Operative Procedure for Pelvic Organ Prolapse Utilizing a MRI-Visible Mesh Implant: Safety and Outcome of Modified Laparoscopic Bilateral Sacropexy

    PubMed Central

    Meyberg-Solomayer, Gabriele; Radosa, Julia; Bader, Werner; Schneider, Guenther; Solomayer, Erich

    2015-01-01

    Introduction. Sacropexy is a generally applied treatment of prolapse, yet there are known possible complications of it. An essential need exists for better alloplastic materials. Methods. Between April 2013 and June 2014, we performed a modified laparoscopic bilateral sacropexy (MLBS) in 10 patients using a MRI-visible PVDF mesh implant. Selected patients had prolapse POP-Q stages II-III and concomitant OAB. We studied surgery-related morbidity, anatomical and functional outcome, and mesh-visibility in MRI. Mean follow-up was 7.4 months. Results. Concomitant colporrhaphy was conducted in 1/10 patients. Anatomical success was defined as POP-Q stage 0-I. Apical success rate was 100% and remained stable. A recurrent cystocele was seen in 1/10 patients during follow-up without need for intervention. Out of 6 (6/10) patients with preoperative SUI, 5/6 were healed and 1/6 persisted. De-novo SUI was seen in 1/10 patients. Complications requiring a relaparoscopy were seen in 2/10 patients. 8/10 patients with OAB were relieved postoperatively. The first in-human magnetic resonance visualization of a prolapse mesh implant was performed and showed good quality of visualization. Conclusion. MLBS is a feasible and safe procedure with favorable anatomical and functional outcome and good concomitant healing rates of SUI and OAB. Prospective data and larger samples are required. PMID:25961042

  5. Amolimogene bepiplasmid, a DNA-based therapeutic encoding the E6 and E7 epitopes from HPV, for cervical and anal dysplasia.

    PubMed

    Alvarez-Salas, Luis M

    2008-12-01

    MGI Pharma Biologics is developing amolimogene bepiplasmid as a potential therapy for HPV-associated diseases, including cervical dysplasia. Amolimogene bepiplasmid is a polymer-encapsulated DNA vaccine consisting of a plasmid expressing a chimeric peptide comprising immunogenic hybrid epitopes from HPV-16 and HPV-18 E6 and E7 proteins and an HLA-DRalpha intracellular trafficking peptide. In phase I and I/II clinical trials of ZYC-101 (the precursor of amolimogene bepiplasmid containing a single epitope from HPV-16 E7) in patients with cervical dysplasia and patients with anal dysplasia, ZYC-101 produced significant histological regression and was safe and well tolerated. Results from this trial led to a phase II clinical trial of amolimogene bepiplasmid in patients with cervical dysplasia. This phase II trial demonstrated that treatment with amolimogene bepiplasmid resolution of disease was not significantly superior to placebo except in the predefined group of women who were less than 25 years of age. A phase II/III clinical trial was ongoing at the time of publication examining amolimogene bepiplasmid in this patient population.

  6. Evaluation of the In Vivo and In Vitro Effects of Fructose on Respiratory Chain Complexes in Tissues of Young Rats.

    PubMed

    Macongonde, Ernesto António; Vilela, Thais Ceresér; Scaini, Giselli; Gonçalves, Cinara Ludvig; Ferreira, Bruna Klippel; Costa, Naithan Ludian Fernandes; de Oliveira, Marcos Roberto; Avila Junior, Silvio; Streck, Emilio Luiz; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda

    2015-01-01

    Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 μmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients.

  7. Randomized Controlled Clinical Trial to Access Efficacy and Safety of Miltefosine in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil

    PubMed Central

    Chrusciak-Talhari, Anette; Dietze, Reynaldo; Chrusciak Talhari, Carolina; da Silva, Roberto Moreira; Gadelha Yamashita, Ellen Priscila; de Oliveira Penna, Gerson; Lima Machado, Paulo Roberto; Talhari, Sinésio

    2011-01-01

    Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15–20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2–12 y/o and 13–65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8–82.7) and 53.6% (95% CI = 33.9–72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony. PMID:21292895

  8. Two-photon excited fluorescence emission from hemoglobin

    NASA Astrophysics Data System (ADS)

    Sun, Qiqi; Zeng, Yan; Zhang, Wei; Zheng, Wei; Luo, Yi; Qu, Jianan Y.

    2015-03-01

    Hemoglobin, one of the most important proteins in blood, is responsible for oxygen transportation in almost all vertebrates. Recently, we discovered two-photon excited hemoglobin fluorescence and achieved label-free microvascular imaging based on the hemoglobin fluorescence. However, the mechanism of its fluorescence emission still remains unknown. In this work, we studied the two-photon excited fluorescence properties of the hemoglobin subunits, heme/hemin (iron (II)/(III) protoporphyrin IX) and globin. We first studied the properties of heme and the similar spectral and temporal characteristics of heme and hemoglobin fluorescence provide strong evidence that heme is the fluorophore in hemoglobin. Then we studied the fluorescence properties of hemin, globin and methemoglobin, and found that the hemin may have the main effect on the methemoglobin fluorescence and that globin has tryptophan fluorescence like other proteins. Finally, since heme is a centrosymmetric molecule, that the Soret band fluorescence of heme and hemoglobin was not observed in the single photon process in the previous study may be due to the parity selection rule. The discovery of heme two-photon excited fluorescence may open a new window for heme biology research, since heme as a cofactor of hemoprotein has many functions, including chemical catalysis, electron transfer and diatomic gases transportation.

  9. Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

    PubMed Central

    Weston, Cody; Weston, Jennifer; Connor, James; Toms, Steven A.; Marko, Nicholas F.

    2016-01-01

    Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10−3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10−5). PMID:27898674

  10. Urban legends series: oral candidosis.

    PubMed

    Manfredi, M; Polonelli, L; Aguirre-Urizar, J M; Carrozzo, M; McCullough, M J

    2013-04-01

    Candida species (spp) are commensal yeast that can only instigate oral infection (oral candidosis - OC) when there is an underlying predisposing condition in the host. We investigated four controversial topics on OC: (i) How can a microbiological determination of OC be made as Candida spp. are commensal yeasts and not all of them form hyphae or pseudohyphae during infection? (ii) Is median rhomboid glossitis (MRG) a manifestation of candidal infection? (iii) Can candidal infection cause palate papillary hyperplasia (PPH)? (iv) What is the best therapeutic treatment for denture-associated erythematous stomatitis (DAES)? Results from extensive literature searches, including a systematic review, suggested the following: (i) the diagnosis of OC merely on the basis of the presence of yeasts is an oversimplification of a complex process. No convincing evidence of a single test or method better able to discriminate the transition from candidal saprophytism to pathogenicity has been reported in the literature; (ii-iii) conclusive evidence of a direct aetiopathogenic relationship between MRG and PPH and candidal infection has not been found; and (iv) only limited evidence is available for any DAES treatment, thus making it impossible to make strong therapeutic recommendations.

  11. Long-term consequences of neonatal fluoxetine exposure in adult rats.

    PubMed

    Ko, Meng-Ching; Lee, Lukas Jyuhn-Hsiarn; Li, Yang; Lee, Li-Jen

    2014-10-01

    Serotonin (5-HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)-type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late-gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX-exposed adult male rats exhibited reduced locomotor activity and depression-like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX-exposed rats. When the levels of 5-HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long-lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI-type antidepressants during pregnancy should be considered.

  12. The Laminar Cortex Model: A New Continuum Cortex Model Incorporating Laminar Architecture

    PubMed Central

    Du, Jiaxin; Vegh, Viktor; Reutens, David C.

    2012-01-01

    Local field potentials (LFPs) are widely used to study the function of local networks in the brain. They are also closely correlated with the blood-oxygen-level-dependent signal, the predominant contrast mechanism in functional magnetic resonance imaging. We developed a new laminar cortex model (LCM) to simulate the amplitude and frequency of LFPs. Our model combines the laminar architecture of the cerebral cortex and multiple continuum models to simulate the collective activity of cortical neurons. The five cortical layers (layer I, II/III, IV, V, and VI) are simulated as separate continuum models between which there are synaptic connections. The LCM was used to simulate the dynamics of the visual cortex under different conditions of visual stimulation. LFPs are reported for two kinds of visual stimulation: general visual stimulation and intermittent light stimulation. The power spectra of LFPs were calculated and compared with existing empirical data. The LCM was able to produce spontaneous LFPs exhibiting frequency-inverse (1/ƒ) power spectrum behaviour. Laminar profiles of current source density showed similarities to experimental data. General stimulation enhanced the oscillation of LFPs corresponding to gamma frequencies. During simulated intermittent light stimulation, the LCM captured the fundamental as well as high order harmonics as previously reported. The power spectrum expected with a reduction in layer IV neurons, often observed with focal cortical dysplasias associated with epilepsy was also simulated. PMID:23093925

  13. CDH1 (E-cadherin) in testicular germ cell neoplasia: suppressed translation of mRNA in pre-invasive carcinoma in situ but increased protein levels in advanced tumours.

    PubMed

    Sonne, Si B; Hoei-Hansen, Christina E; Nielsen, John E; Herlihy, Amy S; Andersson, Anna-Maria; Almstrup, Kristian; Daugaard, Gedske; Skakkebaek, Niels E; Leffers, Henrik; Rajpert-De Meyts, Ewa

    2006-01-01

    E-cadherin (CDH1) is a transmembrane glycoprotein involved in cellular adhesion. In our recent microarray studies of testicular germ cell tumours (TGCTs) and the common precursor carcinoma in situ (CIS), CDH1 mRNA was highly expressed in CIS and embryonal carcinoma. It has previously been reported that the CDH1 protein is not expressed in CIS. To resolve the discrepancy, we performed a detailed analysis of the expression of CDH1 mRNA and protein in a series of normal and neoplastic testes. High expression of CDH1 mRNA in CIS was confirmed by real-time PCR and in situ hybridisation. At the protein level, however, CDH1 was only detected with one of three tested antibodies, but Western blotting analysis with this antibody showed additional bands, suggesting unspecific staining. The levels of a CDH1 protein fragment in serum samples from 58 patients with TGCTs were analysed by ELISA; we found significantly higher levels in patients with advanced disease (stage II/III) when compared to healthy individuals and patients with stage I TGCT. In conclusion, despite high mRNA levels, the CDH1 protein is not expressed in CIS, suggesting translational suppression of CDH1 protein expression. CDH1 serum levels may be a serological marker for staging of TGCT patients.

  14. Molecular classification defines 4 prognostically distinct glioma groups irrespective of diagnosis and grade.

    PubMed

    Mur, Pilar; Mollejo, Manuela; Hernández-Iglesias, Teresa; de Lope, Ángel Rodríguez; Castresana, Javier S; García, Juan F; Fiaño, Concepción; Ribalta, Teresa; Rey, Juan A; Meléndez, Barbara

    2015-03-01

    According to World Health Organization criteria, diffuse gliomas are divided into several histological subtypes, including astrocytomas, oligodendrogliomas, and oligoastrocytomas, and 4 malignancy grades (I-IV). Molecular alterations, such as the isocitrate dehydrogenase gene (IDH) mutation or 1p/19q loss, are found in these tumors but are not included in the current classification system. Recently, mutation of α thalassemia/mental retardation syndrome X-linked (ATRX) gene and its loss of expression have been reported in infiltrating gliomas. We evaluated ATRX protein expression in 272 gliomas and its association with molecular and clinical features. Loss of ATRX expression was more common in tumors with an astrocytic component (astrocytomas II/III, 46.4%; oligoastrocytomas, 47.5%) but was uncommon in oligodendrogliomas (7.3%) and glioblastomas (0.9%). In astrocytic tumors, loss of ATRX expression was significantly associated with longer overall survival. Remarkably, on the basis of IDH mutation, 1p/19q codeletion, and ATRX expression, our study defined 4 molecularly and prognostically different groups of gliomas, showing the relevance of ATRX expression as a new marker for refining the molecular classification of gliomas and for distinguishing clinically distinct prognostic subgroups of patients.

  15. How I treat cryoglobulinemia.

    PubMed

    Muchtar, Eli; Magen, Hila; Gertz, Morie A

    2017-01-19

    Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.

  16. German Translation and Validation of the “Freezing of Gait Questionnaire” in Patients with Parkinson's Disease

    PubMed Central

    Vogler, Anina; Janssens, Jorina; Nyffeler, Thomas; Bohlhalter, Stephan; Vanbellingen, Tim

    2015-01-01

    Background. Freezing of Gait (FOG) is a disabling parkinsonian symptom. The Freezing of Gait Questionnaire (FOG-Q) reliably detects FOG in patients with Parkinson's disease (PD). Objectives. The aim of this study was to develop a German translated version of the FOG-Q and to assess its validity. Methods. The translation was accomplished using forward-backward-translation. The construct validity of the FOG-Q was examined in twenty-seven German native speaking PD patients. Convergent validity was assessed by correlating the FOG-Q with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II-III, the Parkinson Disease Questionnaire 39 (PDQ-39), and the Timed Up and Go Test (TUG). Divergent validity was assessed by correlating the FOG-Q with the MDS-UPDRS I. The internal consistency was measured using Cronbach's alpha (Cα). Results. A good internal structure of the FOG-Q was found (Cα = 0.83). Significant moderate correlations between the FOG-Q and the MDS-UPDRS item 2.13 (freezing) (rs = 0.568, P = 0.002) and between the FOG-Q and the PDQ-39 subscale mobility (rs = 0.516, P = 0.006) were found. The lack of correlation with the MDS-UPDRS I demonstrated good divergent validity. Conclusion. The German FOG-Q is a valid tool to assess FOG in German native speaking PD patients. PMID:25705546

  17. An assessment of transcriptional changes in porcine skin exposed to bromine vapor.

    PubMed

    Rogers, James V; Price, Jennifer A; Wendling, Morgan Q S; Perry, Mark R; Reid, Frances M; Kiser, Robyn C; Graham, John S

    2011-01-01

    Bromine is an industrial chemical that can cause severe cutaneous burns. This study was a preliminary investigation into the effect of cutaneous exposure to bromine vapor using a weanling swine burn model and microarray analysis. Ventral abdominal sites were exposed to a mean calculated bromine vapor concentration of 0.69 g L(-1) for 10 or 20 min. At 48 h postexposure, total RNA from skin samples was isolated, processed, and hybridized to Affymetrix GeneChip Porcine Genome Arrays. Expression analysis revealed that bromine vapor exposure for 10 or 20 min promoted similar transcriptional changes in the number of significantly modulated probe sets. A minimum of 83% of the probe sets was similar for both exposure times. Ingenuity pathways analysis revealed eight common biological functions among the top 10 functions of each experimental group, in which 30 genes were commonly shared among 19 significantly altered signaling pathways. Transcripts encoding heme oxygenase 1, interleukin-1β, interleukin 2 receptor gamma chain, and plasminogen activator inhibitor-1 were identified as common potential therapeutic targets for Phase II/III clinical trial or FDA-approved drugs. The present study is an initial assessment of the transcriptional responses to cutaneous bromine vapor exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

  18. Deficient expression of the small proteoglycan decorin in a case of severe/lethal osteogenesis imperfecta

    SciTech Connect

    Dyne, K.M.; Valli, M.; Forlino, A.; Cetta, G.; Mottes, M.; Kresse, H.

    1996-05-03

    In osteogenesis imperfecta (OI) the effects of mutations in type I collagen genes generally reflect their nature and localization. Unrelated individuals sharing identical mutations present, in general, similar clinical phenotypes. However, in some such cases the clinical phenotype differs. This variable clinical expression could be the result of abnormalities in other connective tissue proteins. Since decorin is a component of connective tissue, binds to type I collagen fibrils and plays a role in matrix assembly, we studied decorin production in skin fibroblasts from OI patients. Cultured fibroblasts from one patient with extremely severe osteogenesis imperfecta (classified as type II/III) who has an {alpha}1(I)gly415ser mutation were found to secrete barely detectable amounts of decorin into culture medium. Western blotting using antibodies raised against decorin confirmed the reduction of the decorin core protein and Northern blot analysis showed decorin mRNA levels below the limit of detection. Cells from a patient, with a less severe phenotype, bearing a mutation in the same position of the triple helix ({alpha}1(1)gly415) expressed decorin normally. The different clinical phenotypes could be due to the differing genetic backgrounds of the patients, so it is tempting to conclude that in our most severely affected patient, the absence of decorin aggravates the clinical phenotype. 34 refs., 4 figs., 1 tab.

  19. The effects of chronic fluoxetine treatment following injury of medial frontal cortex in mice.

    PubMed

    McAllister, Brendan B; Spanswick, Simon C; Patel, Payal P; Barneto, Alison A; Dyck, Richard H

    2015-09-01

    Injury of the brain is a leading cause of long-term disability. Recent evidence indicates that the selective serotonin reuptake inhibitor drug fluoxetine may be beneficial when administered following brain injury. However, its potential to promote recovery and the mechanisms by which it might do so require further characterization. In the present experiment, fluoxetine was administered to mice for 4 weeks following injury of medial frontal cortex (MFC). MFC injury altered behavior, reducing locomotion, decreasing swim speed in the Morris water task, and decreasing anxiety-like behavior in the elevated plus maze. Fluoxetine treatment did not affect these behavioral alterations, but it did increase the social dominance of the injured mice, as assessed by the tube test. Fluoxetine treatment also hastened learning of a T-maze position discrimination task, independently of lesion condition. Anatomically, fluoxetine failed to decrease lesion size, increase the survival of cells born 1-week post injury in the hippocampal dentate gyrus, or reverse the reduction in spine density in layer II/III pyramidal neurons in cingulate cortex caused by the lesions. Fluoxetine did, however, increase the dendritic arborization of these cells, which was reduced in the mice with lesions. Thus, while not all the effects of MFC injury were ameliorated, the behavioral outcome of mice with MFC injuries was improved, and one of the neuroanatomical sequelae of the lesions counteracted, by chronic fluoxetine, further contributing to the evidence that fluoxetine could be a useful treatment following brain injury.

  20. FRETsg: Biomolecular structure model building from multiple FRET experiments

    NASA Astrophysics Data System (ADS)

    Schröder, G. F.; Grubmüller, H.

    2004-04-01

    Fluorescence energy transfer (FRET) experiments of site-specifically labelled proteins allow one to determine distances between residues at the single molecule level, which provide information on the three-dimensional structural dynamics of the biomolecule. To systematically extract this information from the experimental data, we describe a program that generates an ensemble of configurations of residues in space that agree with the experimental distances between these positions. Furthermore, a fluctuation analysis allows to determine the structural accuracy from the experimental error. Program summaryTitle of program: FRETsg Catalogue identifier: ADTU Program obtainable from: CPC Program Library, Queen's University of Belfast, N. Ireland Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADTU Computer: SGI Octane, Pentium II/III, Athlon MP, DEC Alpha Operating system: Unix, Linux, Windows98/NT/XP Programming language used: ANSI C No. of bits in a word: 32 or 64 No. of processors used: 1 No. of bytes in distributed program, including test data, etc.: 11407 No. of lines in distributed program, including test data, etc.: 1647 Distribution format: gzipped tar file Nature of the physical problem: Given an arbitrary number of distance distributions between an arbitrary number of points in three-dimensional space, find all configurations (set of coordinates) that obey the given distances. Method of solution: Each distance is described by a harmonic potential. Starting from random initial configurations, their total energy is minimized by steepest descent. Fluctuations of positions are chosen to generate distance distribution widths that best fit the given values.