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Sample records for successful target clearance

  1. Clearance Pathways and Tumor Targeting of Imaging Nanoparticles

    PubMed Central

    Yu, Mengxiao; Zheng, Jie

    2016-01-01

    A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clinical translational requirements of regulatory agencies. PMID:26149184

  2. Properdin: New roles in pattern recognition and target clearance

    PubMed Central

    Kemper, Claudia; Hourcade, Dennis E.

    2008-01-01

    Properdin was first described over 50 years ago by Louis Pillemer and his collaborators as a vital component of an antibody-independent complement activation pathway. In the 1970’s properdin was shown to be a stabilizing component of the alternative pathway convertases, the central enzymes of the complement cascade. Recently we have reported that properdin can also bind to target cells and microbes, provide a platform for convertase assembly and function, and promote target phagocytosis. Evidence is emerging that suggests that properdin interacts with a network of target ligands, phagocyte receptors, and serum regulators. Here we review the new findings and their possible implications. PMID:18692243

  3. How successful is nuclear targeting by nanocarriers?

    PubMed

    Tammam, Salma N; Azzazy, Hassan M E; Lamprecht, Alf

    2016-05-10

    The nucleus is ultimately the final target for many therapeutics treating various disorders including cancers, heart dysfunction and brain disorders. Owing to their specialized cell uptake and trafficking mechanisms, nanoparticles (NPs) allow drug targeting where degradation sensitive therapeutics could be delivered to their target tissues and cell in active form and sufficient concentration. However, it has recently become increasingly obvious that cytosolic internalization of a drug molecule does not entail its interaction with its subcellular target and hence careful nanoparticle design and optimization is required to enable nuclear targeting. This review, discusses the barriers to NP nuclear delivery; crossing the cell membrane, endo/lysosomal escape, cytoplasmic trafficking and finally nuclear entry focusing on how NP synthesis and modification could allow for bypassing each of the aforementioned barriers and successfully reaching the nucleus. Examples of nuclear targeted NPs are also discussed, stressing on the critical aspects of nuclear targeting and pointing out how the disease state might change the normal NP path and how such change could be exploited to increase efficiency of nuclear targeting. Finally, the criteria set for the evaluation of nanocarriers for nuclear delivery are discussed highlighting that quantitative rather than qualitative evaluation is required to evaluate how successful nanocarriers for nuclear delivery are, particularly with regards to the amount of drug delivered and released in the nucleus. PMID:26995759

  4. Baptist Hospital East conducts successful target marketing.

    PubMed

    Rees, Tom

    2003-01-01

    A targeted marketing program at Baptist Hospital East, Louisville, Ky., has worked successfully to strengthen the hospital's relationships with the employers and employees in the hospital's marketing area. Also, the program strengthens Baptist East's BaptistWorx occupational medicine program and complements the hospital's traditional advertising. PMID:12875166

  5. Effects of skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones.

    PubMed

    Zhang, Dongjian; Jiang, Cuihua; Yang, Shengwei; Gao, Meng; Huang, Dejian; Wang, Xiaoning; Shao, Haibo; Feng, Yuanbo; Sun, Ziping; Ni, Yicheng; Zhang, Jian; Yin, Zhiqi

    2016-07-01

    Necrosis avid agents (NAAs) can be used for diagnose of necrosis-related diseases, evaluation of therapeutic responses and targeted therapeutics of tumor. In order to probe into the effects of molecular skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones, four dianthrone compounds with the same substituents but different skeletal structures, namely Hypericin (Hyp), protohypericin (ProHyp), emodin dianthrone mesomer (ED-1) and emodin dianthrone raceme (ED-2) were synthesized and radioiodinated. Then radioiodinated dianthrones were evaluated in vitro for their necrosis avidity in A549 lung cancer cells untreated and treated with H2O2. Their biodistribution and pharmacokinetic properties were determined in rat models of induced necrosis. In vitro cell assay revealed that destruction of rigid skeleton structure dramatically reduced their necrosis targeting ability. Animal studies demonstrated that destruction of rigid skeleton structure dramatically reduced the necrotic tissue uptake and speed up the clearance from the most normal tissues for the studied compounds. Among these (131)I-dianthrones, (131)I-Hyp exhibited the highest uptake and persistent retention in necrotic tissues. Hepatic infarction could be clearly visualized by SPECT/CT using (131)I-Hyp as an imaging probe. The results suggest that the skeleton structure of Hyp is the lead structure for further structure optimization of this class of NAAs. PMID:26586010

  6. Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue.

    PubMed

    Kerkelä, Erja; Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-07-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  7. Transient Proteolytic Modification of Mesenchymal Stromal Cells Increases Lung Clearance Rate and Targeting to Injured Tissue

    PubMed Central

    Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-01-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  8. The effect of cilia and the mucociliary clearance on successful drug delivery.

    PubMed

    Gizurarson, Sveinbjörn

    2015-01-01

    Nasal mucociliary clearance is one of the most important factors affecting nasal delivery of drugs and vaccines. This is also the most important physiological defense mechanism inside the nasal cavity. It removes inhaled (and delivered) particles, microbes and substances trapped in the mucus. Almost all inhaled particles are trapped in the mucus carpet and transported with a rate of 8-10 mm/h toward the pharynx. This transport is conducted by the ciliated cells, which contain about 100-250 motile cellular appendages called cilia, 0.3 µm wide and 5 µm in length that beat about 1000 times every minute or 12-15 Hz. For efficient mucociliary clearance, the interaction between the cilia and the nasal mucus needs to be well structured, where the mucus layer is a tri-layer: an upper gel layer that floats on the lower, more aqueous solution, called the periciliary liquid layer and a third layer of surfactants between these two main layers. Pharmacokinetic calculations of the mucociliary clearance show that this mechanism may account for a substantial difference in bioavailability following nasal delivery. If the formulation irritates the nasal mucosa, this mechanism will cause the irritant to be rapidly diluted, followed by increased clearance, and swallowed. The result is a much shorter duration inside the nasal cavity and therefore less nasal bioavailability. PMID:25739664

  9. Reducing undesirable hepatic clearance of a tumor-targeted vinca alkaloid via novel saccharopeptidic modifications.

    PubMed

    Leamon, Christopher P; Reddy, Joseph A; Klein, Patrick J; Vlahov, Iontcho R; Dorton, Ryan; Bloomfield, Alicia; Nelson, Melissa; Westrick, Elaine; Parker, Nikki; Bruna, Kristen; Vetzel, Marilynn; Gehrke, Mark; Nicoson, Jeffrey S; Messmann, Richard A; LoRusso, Patricia M; Sausville, Edward A

    2011-02-01

    During a phase I trial of EC145 (a folate-targeted vinca alkaloid conjugate), constipation was identified as the dose-limiting toxicity, probably from a nonfolate receptor-related liver clearance process capable of releasing unconjugated vinca alkaloid from EC145 and shuttling it to the bile. Here, we report on the selective placement of novel carbohydrate segments (1-amino-1-deoxy-glucitolyl-γ-glutamate) spaced in-between the folate and vinca alkaloid moieties of EC145, which yielded a new agent (EC0489) that is equipotent but less toxic than EC145. Whereas both compounds could cure tumor-bearing mice reproducibly, EC0489 differed from EC145 with i) a shorter elimination half-life, ii) approximately 70% decrease in bile clearance, iii) a 4-fold increase in urinary excretion, and iv) improved tolerability in rodents. This combination of improvements justified the clinical evaluation of EC0489 where currently administered dose levels have exceeded the maximal tolerated dose of EC145 by approximately 70%, thereby reflecting the translational benefits to this new approach. PMID:20978169

  10. Targeting CD45RB alters T cell migration and delays viral clearance.

    PubMed

    Lim, Bock; Sutherland, Robyn M; Zhan, Yifan; Deliyannis, Georgia; Brown, Lorena E; Lew, Andrew M

    2006-02-01

    CD45 is a receptor tyrosine phosphatase essential for TCR signaling. One isoform, CD45RB, is down-regulated in memory cells and targeting CD45RB with a specific antibody has been shown to inhibit graft rejection. Its role in immunity to infection, however, has not been tested. Here, we report the effect of anti-CD45RB antibody treatment on the induction of anti-influenza CD8+ T cells and viral clearance. Anti-CD45RB-treated mice had delayed pulmonary viral clearance compared with untreated mice whose infection was completely cleared by day 8 post-infection. In anti-CD45RB-treated mice, the total CD4+ and CD8+ T cell numbers in both the lungs and mediastinal nodes were substantially reduced at days 5 and 8; this effect was less marked for the spleen. CD8+ T cells specific for influenza virus were also reduced compared with the control group in all three organs at day 8. By day 11, when both treated and control groups showed no virus remaining in the lungs, specific CD8+ T cell numbers were at similar low levels. Homing to lymph nodes and lung of dye-labeled T cells was greatly inhibited (by >80%) by anti-CD45RB treatment. This reduced homing corresponded with reduced CD62L and beta1-integrin expression in both uninfected and infected mice. Since CD62L plays a critical role in homing lymphocytes to lymph nodes, and high levels of CD62L and alpha4beta1-integrin are expressed by lymphocytes that home to bronchus-associated lymphoid tissue, we suggest that reduced expression of these molecules is a key explanation for the delay in immune responses. PMID:16361310

  11. Succession Planning and Targeted Leadership Development

    ERIC Educational Resources Information Center

    Wallin, Desna; Cameron, Don W.; Sharples, Kent

    2005-01-01

    A growing number of colleges and boards of trustees are looking to the future by embracing succession planning as the key to assuring college sustainability in an environment that requires global thinking, strategic planning and political savvy. Once confined to the corporate world or to family businesses, and limited to the CEO, succession…

  12. Passive Tumor Targeting of Renal Clearable Luminescent Gold Nanoparticles: Long Tumor Retention and Fast Normal Tissue Clearance

    PubMed Central

    Liu, Jinbin; Yu, Mengxiao; Zhou, Chen; Yang, Shengyang; Ning, Xuhui; Zheng, Jie

    2014-01-01

    Glutathione-coated luminescent gold nanoparticles (GS-AuNPs) of ~ 2.5 nm behave like small dye molecules (IRdye 800CW) in physiological stability and renal clearance, but exhibit much longer tumor retention time and faster normal tissue clearance than the dye molecules, indicating that well-known enhanced permeability and retention (EPR) effect, a unique strength of conventional nanoparticles (NPs) in tumor targeting, still exists in such small NPs. These merits enable the AuNPs to more rapidly detect tumor than the dye molecules without severe accumulation in reticuloendothelial system (RES) organs, holding great promise in cancer diagnosis and therapy. PMID:23506476

  13. Clearance of persistent hepatitis C virus infection using a claudin-1-targeting monoclonal antibody

    PubMed Central

    Mailly, Laurent; Wilson, Garrick K.; Aubert, Philippe; Duong, François H. T.; Calabrese, Diego; Leboeuf, Céline; Fofana, Isabel; Thumann, Christine; Bandiera, Simonetta; Lütgehetmann, Marc; Volz, Tassilo; Davis, Christopher; Harris, Helen J.; Mee, Christopher J.; Girardi, Erika; Chane-Woon-Ming, Béatrice; Ericsson, Maria; Fletcher, Nicola; Bartenschlager, Ralf; Pessaux, Patrick; Vercauteren, Koen; Meuleman, Philip; Villa, Pascal; Kaderali, Lars; Pfeffer, Sébastien; Heim, Markus H.; Neunlist, Michel; Zeisel, Mirjam B.; Dandri, Maura; McKeating, Jane A.; Robinet, Eric; Baumert, Thomas F.

    2015-01-01

    Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3-5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model6 we show that a monoclonal antibody specific for TJ protein claudin-17 eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection via host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy. PMID:25798937

  14. Accelerated Blood Clearance Phenomenon Reduces the Passive Targeting of PEGylated Nanoparticles in Peripheral Arterial Disease.

    PubMed

    Im, Hyung-Jun; England, Christopher G; Feng, Liangzhu; Graves, Stephen A; Hernandez, Reinier; Nickles, Robert J; Liu, Zhuang; Lee, Dong Soo; Cho, Steve Y; Cai, Weibo

    2016-07-20

    Peripheral arterial disease (PAD) is a leading global health concern. Due to limited imaging and therapeutic options, PAD and other ischemia-related diseases may benefit from the use of long circulating nanoparticles as imaging probes and/or drug delivery vehicles. Polyethylene glycol (PEG)-conjugated nanoparticles have shown shortened circulation half-lives in vivo when injected multiple times into a single subject. This phenomenon has become known as the accelerated blood clearance (ABC) effect. The phenomenon is of concern for clinical translation of nanomaterials as it limits the passive accumulation of nanoparticles in many diseases, yet it has not been evaluated using inorganic or organic-inorganic hybrid nanoparticles. Herein, we found that the ABC phenomenon was induced by reinjection of PEGylated long circulating organic-inorganic hybrid nanoparticles, which significantly reduced the passive targeting of (64)Cu-labeled PEGylated reduced graphene oxide-iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) in a murine model of PAD. Positron emission tomography (PET) imaging was performed at 3, 10, and 17 days postsurgical induction of hindlimb ischemia. At day 3 postsurgery, the nanoparticles displayed a long circulation half-life with enhanced accumulation in the ischemic hindlimb. At days 10 and 17 postsurgery, reinjected mice displayed a short circulation half-life and lower accumulation of the nanoparticles in the ischemic hindlimb, in comparison to the naïve group. Also, reinjected mice showed significantly higher liver uptake than the naïve group, indicating that the nanoparticles experienced higher sequestration by the liver in the reinjected group. Furthermore, photoacoustic (PA) imaging and Prussian blue staining confirmed the enhanced accumulation of the nanoparticles in the liver tissue of reinjected mice. These findings validate the ABC phenomenon using long circulating organic-inorganic hybrid nanoparticles upon multiple administrations to the same

  15. The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

    PubMed Central

    Datta-Mannan, Amita; Lu, Jirong; Witcher, Derrick R; Leung, Donmienne; Tang, Ying; Wroblewski, Victor J

    2015-01-01

    The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-by-case basis to improve the design of molecules with increased therapeutic application. PMID:26337808

  16. Serum Human Chorionic Gonadotropin (β- hCG) Clearance Curves in Women with Successfully Expectantly Managed Tubal Ectopic Pregnancies: A Retrospective Cohort Study

    PubMed Central

    Helmy, Samir; Mavrelos, Dimitrios; Sawyer, Elinor; Ben-Nagi, Jara; Koch, Marianne; Day, Andrea; Jurkovic, Davor

    2015-01-01

    Objective To establish clearance curves for serum β -hCG in women with successfully expectantly managed tubal ectopic pregnancies. Design Retrospective cohort study. Non- viable tubal ectopic pregnancy was diagnosed on transvaginal ultrasound. If initial serum β hCG was less than 5000 IU/L and patients were asymptomatic, expectant management was offered. Patients underwent serial β hCG measurements until serum β hCG was less than 20 IU/l, or the urine pregnancy test was negative. Setting Early Pregnancy and Gynaecology Assessment Unit, Kings College Hospital, London (December 1998 to July 2006). Patients We included 161 women with diagnosed non-viable tubal ectopic pregnancy who underwent successful expectant management. Main outcome measure Serum β hCG level. Results Mean initial serum β- hCG was 488 IU/L (41 - 4883) and median serum β hCG clearance time was 19 days (5 - 82). The average half-life of β hCG clearance was 82.5 hours (±SD 50.2) in patients with steadily declining serum β- hCG levels compared to 106.7 hours (±SD 72.0) in patients with primarily plateauing β-hCG levels in the declining phase. However, these differences were not significant (p>0.05). Conclusion We identified a median follow-up of 19 days until serum β hCG clearance in women with tubal ectopic pregnancy and successful expectant management. Although non- significant, women with initially plateauing serum β hCG showed a longer follow-up time until clearance compared to women with steadily declining β hCG levels. This information may serve as a guideline enabling clinicians to predict the length of follow-up for women with tubal ectopic pregnancy and expectant management. PMID:26135923

  17. Guide star targeting success for the HEAO-B observatory

    NASA Technical Reports Server (NTRS)

    Farrenkopf, R. L.; Hoffman, D. P.

    1977-01-01

    The statistics associated with the successful selection and acquisition of guide stars as attitude benchmarks for use in reorientation maneuvers of the HEAO-B observatory are considered as a function of the maneuver angle, initial attitude uncertainties, and the pertinent celestial region. Success likelihoods in excess of 0.99 are predicted assuming anticipated gyro and star tracker error sources. The maneuver technique and guide star selection constraints are described in detail. The results presented are specialized numerically to the HEAO-B observatory. However, the analytical techniques developed are considered applicable to broader classes of spacecraft requiring celestial targeting.

  18. Successes and limitations of targeted cancer therapy in lung cancer.

    PubMed

    Suda, Kenichi; Mitsudomi, Tetsuya

    2014-01-01

    Human cancers usually evolve through multistep processes. These processes are driven by the accumulation of abundant genetic and epigenetic abnormalities. However, some lung cancers depend on a single activated oncogene by somatic mutation, termed 'driver oncogenic mutations', for their proliferation and survival. EGFR(epidermal growth factor receptor) mutations and ALK(anaplastic lymphoma kinase) rearrangement are typical examples of such driver oncogenic mutations found in lung adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs significantly improved treatment outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers harboring EGFR mutations or ALK rearrangement, respectively. Therefore, treatment strategies for lung cancers have dramatically changed from a 'general and empiric' to a 'personalized and evidence-based' approach according to the driver oncogenic mutation. Several novel driver oncogenic mutations, which are candidates as novel targets, such as ERBB2, BRAF, ROS1, and RET, have been discovered. Despite these successes, several limitations have arisen. One example is that some lung cancers do not respond to treatments targeting driver oncogenic mutations, as exemplified in KRAS-mutated lung cancers. Another is resistance to molecular-targeted drugs. Such resistance includes de novo resistance and acquired resistance. A number of molecular mechanisms underlying such resistance have been reported. These mechanisms can be roughly divided into three categories: alteration of the targeted oncogenes themselves by secondary mutations or amplification, activation of an alternative oncogenic signaling track, and conversion of cellular characteristics. Overcoming resistance is a current area of urgent clinical research. PMID:24727987

  19. Estimating Magnetic Polarizability Tensor of Buried Metallic Targets for Land Mine Clearance

    NASA Astrophysics Data System (ADS)

    Dekdouk, B.; Marsh, L. A.; Armitage, D. W.; Peyton, A. J.

    This chapter addresses the problem of identifying metallic objects in buried land mines and discriminating them from clutter using low-frequency electromagnetic induction (EMI) techniques. From dipolar fields, the magnetic polarizability tensor extracted from the target response can be used as a basis for identification. Here, a deterministic nonlinear optimization method is presented to estimate target polarizability matrix and location by fitting a dipole model to EMI data collected above target in a least squares sense. Using finite element simulated data with added synthetic low-frequency noise (10 dB SNR), results show initial guess misestimating target position with few centimeters in the transversal (x, y) plane can be corrected very close to the true location. The method is also able to estimate the polarizability tensor to within 12 % error of the true tensor.

  20. Targeting STAT3 in cancer: how successful are we?

    PubMed Central

    Yue, Peibin; Turkson, James

    2008-01-01

    Background Aberrant activation of the signal transducer and activator of transcription (STAT)3 occurs in many human tumors. Moreover, studies utilizing genetic and pharmacological approaches to modulate constitutive STAT3 activity have provided compelling evidence for the critical role of aberrant STAT3 activity in malignant transformation and tumor progression, and thereby validated STAT3 as a novel cancer drug target. Objective This review is intended to be a full coverage of the efforts to develop direct STAT3 inhibitors and will provide a discussion on the inhibitory modalities developed to date. Methods Review of the literature focused on the modalities and mechanisms that directly target and inhibit the STAT protein or its functions. Results/conclusion While a variety of STAT3 inhibitors have been identified that induce antitumor cell effects in vitro and in vivo, the landscape remains murky. With a few exceptions, most of the STAT3 inhibitors reported to date have not undergone an in vivo efficacy, pharmacology or toxicity testing. Also, there is no evidence, per the published literature of an impending clinical development for the few agents that were reported to exhibit in vivo efficacy. Overall, there is the need for a reassessment of the ongoing strategies to target STAT3 intended not only for refinement, but also for incorporating some new technologies to strengthen our efforts and ensure the success – sooner, rather than later – of identifying suitable anti-STAT3 agents for development into clinically useful anticancer therapeutics. PMID:19053881

  1. Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia

    PubMed Central

    Li, June; van der Wal, Dianne E.; Zhu, Guangheng; Xu, Miao; Yougbare, Issaka; Ma, Li; Vadasz, Brian; Carrim, Naadiya; Grozovsky, Renata; Ruan, Min; Zhu, Lingyan; Zeng, Qingshu; Tao, Lili; Zhai, Zhi-min; Peng, Jun; Hou, Ming; Leytin, Valery; Freedman, John; Hoffmeister, Karin M.; Ni, Heyu

    2015-01-01

    Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP. PMID:26185093

  2. Identifying minefields and verifying clearance: adapting statistical methods for UXO target detection

    NASA Astrophysics Data System (ADS)

    Gilbert, Richard O.; O'Brien, Robert F.; Wilson, John E.; Pulsipher, Brent A.; McKinstry, Craig A.

    2003-09-01

    It may not be feasible to completely survey large tracts of land suspected of containing minefields. It is desirable to develop a characterization protocol that will confidently identify minefields within these large land tracts if they exist. Naturally, surveying areas of greatest concern and most likely locations would be necessary but will not provide the needed confidence that an unknown minefield had not eluded detection. Once minefields are detected, methods are needed to bound the area that will require detailed mine detection surveys. The US Department of Defense Strategic Environmental Research and Development Program (SERDP) is sponsoring the development of statistical survey methods and tools for detecting potential UXO targets. These methods may be directly applicable to demining efforts. Statistical methods are employed to determine the optimal geophysical survey transect spacing to have confidence of detecting target areas of a critical size, shape, and anomaly density. Other methods under development determine the proportion of a land area that must be surveyed to confidently conclude that there are no UXO present. Adaptive sampling schemes are also being developed as an approach for bounding the target areas. These methods and tools will be presented and the status of relevant research in this area will be discussed.

  3. miR-155 suppresses bacterial clearance in Pseudomonas aeruginosa-induced keratitis by targeting Rheb.

    PubMed

    Yang, Kun; Wu, Minhao; Li, Meiyu; Li, Dandan; Peng, Anping; Nie, Xinxin; Sun, Mingxia; Wang, Jinli; Wu, Yongjian; Deng, Qiuchan; Zhu, Min; Chen, Kang; Yuan, Jin; Huang, Xi

    2014-07-01

    miR-155 (microRNA-155) is an important noncoding RNA in regulating host inflammatory responses. However, its regulatory role in ocular infection remains unclear. Our study first explored the function of miR-155 in Pseudomonas aeruginosa-induced keratitis, one of the most common sight-threatening ocular diseases. We found that miR-155 expression was enhanced in human and mouse corneas after P. aeruginosa infection and was mainly expressed in macrophages but not neutrophils. In vivo studies demonstrated that miR-155 knockout mice displayed more resistance to P. aeruginosa keratitis, with a higher inducible nitric oxide synthase level and a lower bacterial burden. More importantly, in vitro data indicated that miR-155 suppressed the macrophage-mediated bacterial phagocytosis and intracellular killing of P. aeruginosa by targeting Rheb (Ras homolog enriched in brain). To the best of our knowledge, this is the first study to explore the role of miR-155 in bacterial keratitis, which may provide a promising target for clinical treatment of P. aeruginosa keratitis and other infectious diseases. PMID:24403554

  4. Telling ingratiating lies: effects of target sex and target attractiveness on verbal and nonverbal deceptive success.

    PubMed

    DePaulo, B M; Stone, J I; Lassiter, G D

    1985-05-01

    Male and female "senders" described their opinions on four controversial issues to target persons. Each sender expressed sincere agreement with the target on one of the issues and sincere disagreement on another (truthful messages), and also pretended to agree with the partner on one of the issues (an ingratiating lie) and pretended to disagree on another (a noningratiating lie). Groups of judges then rated the sincerity of each message on the basis of information available from one of four different channels: verbal (words only, in transcript form), audio (audiotape only), visual (videotape with no sound), and audiovisual (videotape with sound). Results showed that (a) lies told by women were more readily detected than lies told by men, (b) lies told to opposite-sex targets were more easily detected than lies to same-sex targets, and (c) ingratiating lies were more successfully detected than were noningratiating lies, particularly when told to attractive targets. Furthermore, when senders talked to opposite-sex (relative to same-sex) targets, their lies were most easily detected from the three channels that included nonverbal cues. For ingratiating (relative to noningratiating) lies, detectability was greatest for the channels that included visual nonverbal cues. Senders addressing attractive targets were perceived as less sincere than senders addressing unattractive targets, both when lying and when telling the truth, and this difference in the degree of sincerity conveyed was especially pronounced in the channels that included nonverbal cues. Results are discussed in terms of the effects of motivation on verbal and nonverbal communicative success. PMID:3998987

  5. Development of a successive targeting liposome with multi-ligand for efficient targeting gene delivery

    PubMed Central

    Ma, Kun; Shen, Haijun; Shen, Song; Xie, Men; Mao, Chuanbin; Qiu, Liyan; Jin, Yi

    2012-01-01

    Background A successful gene delivery system needs to breakthrough several barriers to allow efficient transgenic expression. In the present study, successive targeting liposomes (STL) were constructed by integrating various targeting groups into a nanoparticle to address this issue. Methods Polyethylenimine (PEI) 1800-triamcinolone acetonide (TA) with nuclear targeting capability was synthesized by a two-step reaction. Lactobionic acid was connected with cholesterol to obtain a compound of [(2-lactoylamido) ethylamino]formic acid cholesterol ester (CHEDLA) with hepatocyte-targeting capability. The liposome was modified with PEI 1800-TA and CHEDLA to prepare successive targeting liposome (STL). Its physicochemical properties and transfection efficiency were investigated both in vitro and in vivo. Results The diameter of STL was approximately 100 nm with 20 mV of potential. The confocal microscopy observation and potential assay verified that lipid bilayer of STL was decorated with PEI 1800-TA. Cytotoxicity of STL was significantly lower than that of PEI 1800-TA and PEI 25K. The transfection efficiency of 10% CHEDLA STL in HepG2 cells was the higher than of the latter two with serum. Its transfection efficiency was greatly reduced with excessive free galactose, indicating that STL was absorbed via galactose receptor-mediated endocytosis. The in vivo study in mice showed that 10% CHEDLA STL had better transgenic expression in liver than the other carriers. Conclusions STL with multi-ligand was able to overcome the various barriers to target nucleus and special cells and present distinctive transgenic expression. Therefore, it has a great potential for gene therapy as a nonviral carrier. PMID:21574214

  6. ICP-MS analysis of lanthanide-doped nanoparticles: A quantitative and multiplexing approach to investigate biodistribution, blood clearance, and targeting

    NASA Astrophysics Data System (ADS)

    Crayton, Samuel

    The rapidly progressing field of nanotechnology promises to revolutionize healthcare in the 21st century, with applications in the prevention, diagnosis, and treatment of a wide range of diseases. However, before nanoparticulate agents can be brought into clinical use, they must first be developed, optimized, and evaluated in animal models. In the typical pre-clinical paradigm, almost all of the optimization is done at the in vitro level, with only a few select agents reaching the level of animal studies. Since only one experimental nanoparticle formulation can be investigated in a single animal, and in vivo experiments have relatively higher complexity, cost, and time requirements, it is not feasible to evaluate a very large number of agents at the in vivo stage. A major drawback of this approach, however, is that in vitro assays do not always accurately predict how a nanoparticle will perform in animal studies. Therefore, a method that allows many agents to be evaluated in a single animal subject would allow for much more efficient and predictive optimization of nanoparticles. We have found that by incorporating lanthanide tracer metals into nanoparticle formulations, we are successfully able to use inductively coupled plasma mass spectrometry (ICP-MS) to quantitatively determine a nanoparticle's blood clearance kinetics, biodistribution, and tumor delivery. This approach was applied to evaluate both passive and active tumor targeting, as well as metabolically directed targeting of nanoparticles to low pH tumor microenvironments. Importantly, we found that these in vivo measurements could be made for many nanoparticle formulations simultaneously, in single animals, due to the high-order multiplexing capability of mass spectrometry. This approach allowed for efficient and reproducible comparison of performance between different nanoparticle formulations, by eliminating the effects of subject-to-subject variability. In the future, we envision that this "higher

  7. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody.

    PubMed

    Mailly, Laurent; Xiao, Fei; Lupberger, Joachim; Wilson, Garrick K; Aubert, Philippe; Duong, François H T; Calabrese, Diego; Leboeuf, Céline; Fofana, Isabel; Thumann, Christine; Bandiera, Simonetta; Lütgehetmann, Marc; Volz, Tassilo; Davis, Christopher; Harris, Helen J; Mee, Christopher J; Girardi, Erika; Chane-Woon-Ming, Béatrice; Ericsson, Maria; Fletcher, Nicola; Bartenschlager, Ralf; Pessaux, Patrick; Vercauteren, Koen; Meuleman, Philip; Villa, Pascal; Kaderali, Lars; Pfeffer, Sébastien; Heim, Markus H; Neunlist, Michel; Zeisel, Mirjam B; Dandri, Maura; McKeating, Jane A; Robinet, Eric; Baumert, Thomas F

    2015-05-01

    Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy. PMID:25798937

  8. Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance.

    PubMed

    Li, Xiaoling; Liu, Hongmei; Fischhaber, Paula L; Tang, Tie-Shan

    2015-09-01

    Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3), an autosomal dominant neurological disorder, is caused by an abnormal expanded polyglutamine (polyQ) repeat in the ataxin-3 protein. The length of the expanded polyQ stretch correlates positively with the severity of the disease and inversely with the age at onset. To date, we cannot fully explain the mechanism underlying neurobiological abnormalities of this disease. Yet, accumulating reports have demonstrated the functions of ataxin-3 protein in the chaperone system, ubiquitin-proteasome system, and aggregation-autophagy, all of which suggest a role of ataxin-3 in the clearance of misfolded proteins. Notably, the SCA3 pathogenic form of ataxin-3 (ataxin-3(exp)) impairs the misfolded protein clearance via mechanisms that are either dependent or independent of its deubiquitinase (DUB) activity, resulting in the accumulation of misfolded proteins and the progressive loss of neurons in SCA3. Some drugs, which have been used as activators/inducers in the chaperone system, ubiquitin-proteasome system, and aggregation-autophagy, have been demonstrated to be efficacious in the relief of neurodegeneration diseases like Huntington's disease (HD), Parkinson's (PD), Alzheimer's (AD) as well as SCA3 in animal models and clinical trials, putting misfolded protein clearance on the list of potential therapeutic targets. Here, we undertake a comprehensive review of the progress in understanding the physiological functions of ataxin-3 in misfolded protein clearance and how the polyQ expansion impairs misfolded protein clearance. We then detail the preclinical studies targeting the elimination of misfolded proteins for SCA3 treatment. We close with future considerations for translating these pre-clinical results into therapies for SCA3 patients. PMID:26123252

  9. An Evaluation of the Target Success Mentor Program.

    ERIC Educational Resources Information Center

    Jackson, Jerlando F. L.; Mathews, Jerry G.

    Auburn University's Office of Minority Advancement, in conjunction with Auburn Junior High School, implemented a joint program to assist at-risk African-American male students while at Auburn Junior High School. Using the help of faculty and trained college student mentors, the Success in Reading Program was designed to enhance successful…

  10. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  11. Modeling the impact of hepatitis C viral clearance on end-stage liver disease in an HIV co-infected cohort with Targeted Maximum Likelihood Estimation

    PubMed Central

    Schnitzer, Mireille E; Moodie, Erica EM; van der Laan, Mark J; Platt, Robert W; Klein, Marina B

    2013-01-01

    Summary Despite modern effective HIV treatment, hepatitis C virus (HCV) co-infection is associated with a high risk of progression to end-stage liver disease (ESLD) which has emerged as the primary cause of death in this population. Clinical interest lies in determining the impact of clearance of HCV on risk for ESLD. In this case study, we examine whether HCV clearance affects risk of ESLD using data from the multicenter Canadian Co-infection Cohort Study. Complications in this survival analysis arise from the time-dependent nature of the data, the presence of baseline confounders, loss to follow-up, and confounders that change over time, all of which can obscure the causal effect of interest. Additional challenges included non-censoring variable missingness and event sparsity. In order to efficiently estimate the ESLD-free survival probabilities under a specific history of HCV clearance, we demonstrate the doubly-robust and semiparametric efficient method of Targeted Maximum Likelihood Estimation (TMLE). Marginal structural models (MSM) can be used to model the effect of viral clearance (expressed as a hazard ratio) on ESLD-free survival and we demonstrate a way to estimate the parameters of a logistic model for the hazard function with TMLE. We show the theoretical derivation of the efficient influence curves for the parameters of two different MSMs and how they can be used to produce variance approximations for parameter estimates. Finally, the data analysis evaluating the impact of HCV on ESLD was undertaken using multiple imputations to account for the non-monotone missing data. PMID:24571372

  12. New ways to successfully target tumor vasculature in ovarian cancer

    PubMed Central

    Yang, Xiaoyun; Shen, Fangrong; Hu, Wei; Coleman, Robert L.; Sood, Anil K.

    2015-01-01

    Purpose of review The aim of this paper was to review the recent literature on potential therapeutic strategies for overcoming resistance to anti-VEGF drugs in ovarian cancer. Recent findings Although clinical benefits of anti-VEGF therapy were observed in ovarian cancer treatment trials, this use yielded only modest improvement in progression-free survival, and with the exception of cediranib no effect on overall survival. Adaptive resistance and escape from anti-angiogenesis therapy is likely a multifactorial process, including induction of hypoxia, vascular modulators and the immune response. New drugs targeting the tumor vasculature or other components of the surrounding microenvironment have shown promising results. Summary When to start and end antiangiogenesis therapy and the choice of optimal treatment combinations remain controversial. Further evaluation of personalized novel angiogenesis-based therapy is warranted. Defining the critical interaction of these agents and pathways and the appropriate predictive markers will become an increasingly important objective for effective treatment. PMID:25502429

  13. Renal Clearance of Nanoparticles

    PubMed Central

    Choi, Hak Soo; Liu, Wenhao; Misra, Preeti; Tanaka, Eiichi; Zimmer, John P.; Ipe, Binil Itty; Bawendi, Moungi G.; Frangioni, John V.

    2008-01-01

    SUMMARY The field of nanotechnology holds great promise for the diagnosis and treatment of human disease. However, the size and charge of most nanoparticles preclude their efficient clearance from the body as intact nanoparticles. Without such clearance or their biodegradation into biologically benign components, toxicity is potentially amplified and radiological imaging is hindered. Using quantum dots (QDs) as a model system, we have precisely defined the requirements for renal filtration and urinary excretion of inorganic, metal-containing nanoparticles. Zwitterionic or neutral organic coatings prevented adsorption of serum proteins, which otherwise increased hydrodynamic diameter (HD) by over 15 nm and prevented renal excretion. A final HD smaller than 5.5 nm resulted in rapid and efficient urinary excretion, and elimination of QDs from the body. This study provides a foundation for the design and development of biologically targeted nanoparticles for biomedical applications. PMID:17891134

  14. A Blueprint for Success. Aligning Our Targets: Proficiency, Learning, Assessment--The Memphis City School's Story

    ERIC Educational Resources Information Center

    Villarreal, Alyssa

    2013-01-01

    This article peers through the lens of one district's journey of World Languages program refinement, and identifies a blueprint for success by aligning targets. The author begins by proposing the following questions: (1) Is your program where you want it to be? (2) Is it producing desired results? and (3) Are students yielding the greatest results…

  15. 48 CFR 52.216-17 - Incentive Price Revision-Successive Targets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Incentive Price Revision-Successive Targets. 52.216-17 Section 52.216-17 Federal Acquisition Regulations System FEDERAL ACQUISITION... liquidation of progress payments, then that portion may, instead of being refunded, be added to...

  16. 48 CFR 16.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ACQUISITION REGULATION CONTRACTING METHODS AND CONTRACT TYPES TYPES OF CONTRACTS Incentive Contracts 16.403-2... (successive targets) contract specifies the following elements, all of which are negotiated at the outset: (i... adjustment under other contract clauses providing for equitable adjustment or other revision of the...

  17. Appropriately Targeting Group Interventions for Academic Success Adopting the Clinical Model and PAR Profiles

    ERIC Educational Resources Information Center

    Johnson, Craig W.; Johnson, Ronald; Steigman, Michael; Odo, Chioma; Vijayan, Suvendra; Tata, Devadatta V.

    2016-01-01

    Prevalence of academic risk (PAR) group profiles provide data enabling empirically based group-specialized prescriptions for targeted academic success interventions to increase student retention, completion, and graduation rates, while improving allocation of institutional resources. Postsecondary student attrition engenders student debt,…

  18. 48 CFR 216.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Fixed-price incentive (successive targets) contracts. 216.403-2 Section 216.403-2 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES TYPES...

  19. 48 CFR 216.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Fixed-price incentive (successive targets) contracts. 216.403-2 Section 216.403-2 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES TYPES...

  20. 48 CFR 216.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Fixed-price incentive (successive targets) contracts. 216.403-2 Section 216.403-2 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES TYPES...

  1. 48 CFR 216.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Fixed-price incentive (successive targets) contracts. 216.403-2 Section 216.403-2 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES TYPES...

  2. 48 CFR 216.403-2 - Fixed-price incentive (successive targets) contracts.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Fixed-price incentive (successive targets) contracts. 216.403-2 Section 216.403-2 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACTING METHODS AND CONTRACT TYPES TYPES...

  3. An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets

    PubMed Central

    Bradley, Stuart

    2015-01-01

    Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an “actuator” interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator “firings”) to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a “cost function” is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs. PMID:26610500

  4. siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

    NASA Astrophysics Data System (ADS)

    Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

    2014-05-01

    The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

  5. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells

    SciTech Connect

    Witasp, Erika; Kupferschmidt, Natalia; Bengtsson, Linnea; Hultenby, Kjell; Smedman, Christian; Paulie, Staffan; Garcia-Bennett, Alfonso E.; Fadeel, Bengt

    2009-09-15

    Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

  6. Highly fluorescent resorcinarene cavitand nanocapsules with efficient renal clearance

    NASA Astrophysics Data System (ADS)

    Mahadevan, Kalpana; Patthipati, Venkata Suresh; Han, Sangbum; Swanson, R. James; Whelan, Eoin C.; Osgood, Christopher; Balasubramanian, Ramjee

    2016-08-01

    Nanomaterial based imaging approaches hold substantial promise in addressing current diagnostic and therapeutic challenges. One of the key requirements for the successful clinical translation of nanomaterials is their complete clearance from the body within a reasonable time period preferably via the renal filtration route. This article describes the synthesis of highly fluorescent, water soluble, resorcinarene cavitand nanocapsules and demonstrates their effective renal clearance in mice. The synthesis and functionalization of nanocapsules was accomplished in a one-pot operation via thiol-ene reactions without involving self-assembly, sacrificial templates or emulsions. Water soluble resorcinarene cavitand nanocapsules obtained by this approach were covalently functionalized with Alexa Fluor 750. Highly fluorescent nanocapsules with hydrodynamic diameters of 122 nm and 68 nm and extinction coefficients of 1.3 × 109 M‑1 cm‑1 and 1.5 × 108 M‑1 cm‑1 respectively were prepared by varying the reaction conditions. The in vivo biodistribution and clearance of these nanocapsules in mice followed by whole-body fluorescence imaging showed that they were both cleared renally within a few hours. Given the inherent encapsulation capabilities of nanocapsules, the renal clearance demonstrated in this work opens up new opportunities for their theranostic applications especially for targeting and treating the urinary tract.

  7. Highly fluorescent resorcinarene cavitand nanocapsules with efficient renal clearance.

    PubMed

    Mahadevan, Kalpana; Patthipati, Venkata Suresh; Han, Sangbum; Swanson, R James; Whelan, Eoin C; Osgood, Christopher; Balasubramanian, Ramjee

    2016-08-19

    Nanomaterial based imaging approaches hold substantial promise in addressing current diagnostic and therapeutic challenges. One of the key requirements for the successful clinical translation of nanomaterials is their complete clearance from the body within a reasonable time period preferably via the renal filtration route. This article describes the synthesis of highly fluorescent, water soluble, resorcinarene cavitand nanocapsules and demonstrates their effective renal clearance in mice. The synthesis and functionalization of nanocapsules was accomplished in a one-pot operation via thiol-ene reactions without involving self-assembly, sacrificial templates or emulsions. Water soluble resorcinarene cavitand nanocapsules obtained by this approach were covalently functionalized with Alexa Fluor 750. Highly fluorescent nanocapsules with hydrodynamic diameters of 122 nm and 68 nm and extinction coefficients of 1.3 × 10(9) M(-1) cm(-1) and 1.5 × 10(8) M(-1) cm(-1) respectively were prepared by varying the reaction conditions. The in vivo biodistribution and clearance of these nanocapsules in mice followed by whole-body fluorescence imaging showed that they were both cleared renally within a few hours. Given the inherent encapsulation capabilities of nanocapsules, the renal clearance demonstrated in this work opens up new opportunities for their theranostic applications especially for targeting and treating the urinary tract. PMID:27378394

  8. Therapeutic hypothermia and targeted temperature management in traumatic brain injury: Clinical challenges for successful translation.

    PubMed

    Dietrich, W Dalton; Bramlett, Helen M

    2016-06-01

    The use of therapeutic hypothermia (TH) and targeted temperature management (TTM) for severe traumatic brain injury (TBI) has been tested in a variety of preclinical and clinical situations. Early preclinical studies showed that mild reductions in brain temperature after moderate to severe TBI improved histopathological outcomes and reduced neurological deficits. Investigative studies have also reported that reductions in post-traumatic temperature attenuated multiple secondary injury mechanisms including excitotoxicity, free radical generation, apoptotic cell death, and inflammation. In addition, while elevations in post-traumatic temperature heightened secondary injury mechanisms, the successful implementation of TTM strategies in injured patients to reduce fever burden appear to be beneficial. While TH has been successfully tested in a number of single institutional clinical TBI studies, larger randomized multicenter trials have failed to demonstrate the benefits of therapeutic hypothermia. The use of TH and TTM for treating TBI continues to evolve and a number of factors including patient selection and the timing of the TH appear to be critical in successful trial design. Based on available data, it is apparent that TH and TTM strategies for treating severely injured patients is an important therapeutic consideration that requires more basic and clinical research. Current research involves the evaluation of alternative cooling strategies including pharmacologically-induced hypothermia and the combination of TH or TTM approaches with more selective neuroprotective or reparative treatments. This manuscript summarizes the preclinical and clinical literature emphasizing the importance of brain temperature in modifying secondary injury mechanisms and in improving traumatic outcomes in severely injured patients. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26746342

  9. Manipulating target size influences perceptions of success when learning a dart-throwing skill but does not impact retention.

    PubMed

    Ong, Nicole T; Lohse, Keith R; Hodges, Nicola J

    2015-01-01

    Positive feedback or experiences of success during skill acquisition have been shown to benefit motor skill learning. In this study, our aim was to manipulate learners' success perceptions through a minor adjustment to goal criterion (target size) in a dart-throwing task. Two groups of novice participants practiced throwing at a large (easy) or a small (difficult) target from the same distance. In reference to the origin/center of the target, the practice targets were alike in objective difficulty and indeed participants in both groups were not different in their objective practice performance (i.e., radial error from the center). Although the groups experienced markedly different success rates, with the large target group experiencing more hits and reporting greater confidence (or self-efficacy) than the small target group, these practice effects were not carried into longer-term retention, which was assessed after a 1-week delay. For success perceptions to moderate or benefit motor learning, we argue that unambiguous indicators of positive performance are necessary, especially for tasks where intrinsic feedback about objective error is salient. PMID:26441753

  10. Manipulating target size influences perceptions of success when learning a dart-throwing skill but does not impact retention

    PubMed Central

    Ong, Nicole T.; Lohse, Keith R.; Hodges, Nicola J.

    2015-01-01

    Positive feedback or experiences of success during skill acquisition have been shown to benefit motor skill learning. In this study, our aim was to manipulate learners’ success perceptions through a minor adjustment to goal criterion (target size) in a dart-throwing task. Two groups of novice participants practiced throwing at a large (easy) or a small (difficult) target from the same distance. In reference to the origin/center of the target, the practice targets were alike in objective difficulty and indeed participants in both groups were not different in their objective practice performance (i.e., radial error from the center). Although the groups experienced markedly different success rates, with the large target group experiencing more hits and reporting greater confidence (or self-efficacy) than the small target group, these practice effects were not carried into longer-term retention, which was assessed after a 1-week delay. For success perceptions to moderate or benefit motor learning, we argue that unambiguous indicators of positive performance are necessary, especially for tasks where intrinsic feedback about objective error is salient. PMID:26441753

  11. Successful Combination of Nucleic Acid Amplification Test Diagnostics and Targeted Deferred Neisseria gonorrhoeae Culture

    PubMed Central

    Wind, Carolien M.; de Vries, Henry J. C.; Schim van der Loeff, Maarten F.; Unemo, Magnus

    2015-01-01

    Nucleic acid amplification tests (NAATs) are recommended for the diagnosis of N. gonorrhoeae infections because of their superior sensitivity. Increasing NAAT use causes a decline in crucial antimicrobial resistance (AMR) surveillance data, which rely on culture. We analyzed the suitability of the ESwab system for NAAT diagnostics and deferred targeted N. gonorrhoeae culture to allow selective and efficient culture based on NAAT results. We included patients visiting the STI Clinic Amsterdam, The Netherlands, in 2013. Patient characteristics and urogenital and rectal samples for direct N. gonorrhoeae culture, standard NAAT, and ESwab were collected. Standard NAAT and NAAT on ESwab samples were performed using the Aptima Combo 2 assay for N. gonorrhoeae and C. trachomatis. Two deferred N. gonorrhoeae cultures were performed on NAAT-positive ESwab samples after storage at 4°C for 1 to 3 days. We included 2,452 samples from 1,893 patients. In the standard NAAT, 107 samples were N. gonorrhoeae positive and 284 were C. trachomatis positive. The sensitivities of NAAT on ESwab samples were 83% (95% confidence interval [CI], 75 to 90%) and 87% (95% CI, 82 to 90%), respectively. ESwab samples were available for 98 of the gonorrhea-positive samples. Of these, 82% were positive in direct culture and 69% and 56% were positive in the 1st and 2nd deferred cultures, respectively (median storage times, 27 and 48 h, respectively). Deferred culture was more often successful in urogenital samples or when the patient had symptoms at the sampling site. Deferred N. gonorrhoeae culture of stored ESwab samples is feasible and enables AMR surveillance. To limit the loss in NAAT sensitivity, we recommend obtaining separate samples for NAAT and deferred culture. PMID:25832300

  12. In vivo Biodistribution and Clearance Studies using Multimodal ORMOSIL Nanoparticles

    PubMed Central

    Kumar, Rajiv; Roy, Indrajit; Ohulchanskky, Tymish Y.; Vathy, Lisa A.; Bergey, Earl J.; Sajjad, Munawwar; Prasad, Paras N

    2010-01-01

    Successful translation of the use of nanoparticles from laboratories to clinics requires exhaustive and elaborate studies involving the biodistribution, clearance and biocompatibility of nanoparticles for in vivo biomedical applications. We report here the use of multimodal organically modified silica (ORMOSIL) nanoparticles for in vivo bioimaging, biodistribution, clearance and toxicity studies. We have synthesized ORMOSIL nanoparticles with diameters of 20-25 nm, conjugated with near infra-red (NIR) fluorophores and radiolabelled them with 124I, for optical and PET imaging in vivo. The biodistribution of the non targeted nanoparticles was studied in non-tumored nude mice by optical fluorescence imaging, as well by measuring the radioactivity from harvested organs. Biodistribution studies showed a greater accumulation of nanoparticles in liver, spleen and stomach than in kidney, heart and lungs. The clearance studies carried out over a period of 15 days indicated hepatobiliary excretion of the nanoparticles. Selected tissues were analyzed for any potential toxicity by histological analysis, which confirmed the absence of any adverse effect or any other abnormalities in the tissues. The results demonstrate that these multimodal nanoparticles have potentially ideal attributes for use as biocompatible probes for in vivo imaging. PMID:20088598

  13. Controls Considerations for Turbine Active Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.

    2004-01-01

    This presentation discusses active control of turbine tip clearance from a control systems perspective. It is a subset of charts that were presented at the 2003 meeting of the International Society of Air Breathing Engines which was held August 31 through September 5 in Cleveland, Ohio. The associated reference paper is cited at the end of the presentation. The presentation describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, it is believed that the technologies developed as part of this research will benefit a broad spectrum of current and future turbomachinery. The first part of the presentation discusses the concept of tip clearance, problems associated with it, and the benefits of controlling it. It lays out a framework for implementing tip clearance controls that enables the implementation to progress from purely analytical to hardware-in-the-loop to fully experimental. And it briefly discusses how the technologies developed will be married to the previously described ACC Test Rig for hardware-in-the-loop demonstrations. The final portion of the presentation, describes one of the key technologies in some detail by presenting equations and results for a functional dynamic model of the tip clearance phenomena. As shown, the model exhibits many of the clearance dynamics found in commercial gas turbine engines. However, initial attempts to validate the model identified limitations that are being addressed to make the model more realistic.

  14. Radioaerosol delivery and clearance in patients with respiratory failure

    SciTech Connect

    Jacobs, M.P.; Tennenberg, S.D.; Baughman, R.P.

    1987-12-01

    A technique for radioaerosol delivery to patients requiring mechanical ventilation is described. Ventilation images and pulmonary radioaerosol clearance rates were successfully obtained in 35 patients regardless of ventilator type or level of positive end-expiratory pressure (PEEP). Those patients with noncardiogenic pulmonary edema (NPE) had significantly increased clearance rates relative to those patients in whom NPE was not present.

  15. Assessing the Effectiveness of Targeted Intrusive Advising and Student Success Using an Early Intervention Program

    ERIC Educational Resources Information Center

    Poole, Jesse

    2015-01-01

    The institution in this study is a medium size, public liberal arts institution located in a rural setting. At the beginning of Fall 2012 term, 5,366 undergraduate and 922 graduate students were enrolled in the university's ten-week quarter system. In an attempt to increase student success and retention, the institution implemented a student…

  16. Speaking Spontaneously in the Modern Foreign Languages Classroom: Tools for Supporting Successful Target Language Conversation

    ERIC Educational Resources Information Center

    Christie, Colin

    2016-01-01

    This article reports on the findings of a study into the conditions which promote spontaneous learner talk in the target language in the modern foreign languages (MFL) classroom. A qualitative case study approach was adopted. French lessons, with school students aged 11-16 years old, were observed and analysed with the aim of identifying tools and…

  17. Delivering therapy to target: improving the odds for successful drug development.

    PubMed

    Raghavan, Raghu; Brady, Martin L; Sampson, John H

    2016-07-01

    The direct delivery of drugs and other agents into tissue (in contrast to systemic administration) has been used in clinical trials for brain cancer, neurodegenerative diseases and peripheral tumors. However, continuing evidence suggests that clinical efficacy depends on adequate delivery to a target. Inadequate delivery may have doomed otherwise effective drugs, through failure to distinguish drug inefficacy from poor distribution at the target. Conventional pretreatment clinical images of the patient fail to reveal the complexity and diversity of drug transport pathways in tissue. We discuss the richness of these pathways and argue that development and patient treatment can be sped up and improved by: using quantitative as well as 'real-time' imaging; customized simulations using data from that imaging; and device designs that optimize the drug-device combination. PMID:27403630

  18. Improved clearance of radiolabeled biotinylated monoclonal antibody following the infusion of avidin as a {open_quotes}chase{close_quotes} without decreased accumulation in the target tumor

    SciTech Connect

    Kobayashi, Hisataka; Sakahara, Harumi; Hosono, Makoto

    1994-10-01

    The techniques of radioimmunoimaging and radioimmunotherapy suffer from prolonged high background radioactivity because intravenously injected antibodies remain in the circulation and in the organs far longer than necessary for effective binding to the target. To decrease background and increase radionuclide excretion without decreasing the dose of radioactivity delivered to the target tumor, we used radiolabeled biotinylated antibodies followed by a {open_quotes}chase{close_quotes} avidin injection. A mouse monoclonal antibody, OST7 (lgG1), which reacts with human osteosarcoma, was biotinylated and labeled with {sup 125}I, {sup 131}I or {sup 22m}Tc. Radiolabeled biotinylated OST7 (10 {mu}g) was administered intravenously into nude mice bearing human osteosarcomas and 30 {mu}g of avidin was injected intravenously 6 or 24 hr later. Following avidin injection in mice pretreated with radiolabeled biotinylated antibodies, radioactivity was promptly cleared from the blood and deposited in the liver and spleen, after which radioiodine was rapidly detached from the antibody and excreted in the urine. The tumor-to-blood ratios at 6 and 24 hr after the injection of {sup 125}I-labeled biotinylated OST7 increased compared with the values before the avidin chase without any loss of tumor radioactivity. Furthermore, the tumor -to-background radioactivity ratio was improved and better images were obtained more rapidly after the injection of radiolabeled biotiny-lated antibodies than with conventional immunoscintigraphy. This method may find application in clinical radio-immunoimaging, especially using short half-life radionuclides such as {sup 39m}Tc and {sup 123}I. 24 refs., 8 figs., 3 tabs.

  19. Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget's disease.

    PubMed

    Watanabe, Satomi; Takeda, Masayuki; Takahama, Takayuki; Iwasa, Tsutomu; Tsurutani, Junji; Tanizaki, Junko; Shimizu, Toshio; Sakai, Kazuko; Wada, Yoshitaka; Isogai, Noritaka; Nishio, Kazuto; Nakagawa, Kazuhiko

    2016-06-01

    Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events. PMID:26856856

  20. THE ELM SURVEY. III. A SUCCESSFUL TARGETED SURVEY FOR EXTREMELY LOW MASS WHITE DWARFS

    SciTech Connect

    Brown, Warren R.; Kenyon, Scott J.; Kilic, Mukremin; Allende Prieto, Carlos E-mail: skenyon@cfa.harvard.edu E-mail: callende@iac.es

    2012-01-10

    Extremely low mass (ELM) white dwarfs (WDs) with masses < 0.25 M{sub Sun} are rare objects that result from compact binary evolution. Here, we present a targeted spectroscopic survey of ELM WD candidates selected by color. The survey is 71% complete and has uncovered 18 new ELM WDs. Of the seven ELM WDs with follow-up observations, six are short-period binaries and four have merger times less than 5 Gyr. The most intriguing object, J1741+6526, likely has either a pulsar companion or a massive WD companion making the system a possible supernova Type Ia or an Ia progenitor. The overall ELM survey has now identified 19 double degenerate binaries with <10 Gyr merger times. The significant absence of short orbital period ELM WDs at cool temperatures suggests that common envelope evolution creates ELM WDs directly in short period systems. At least one-third of the merging systems are halo objects, thus ELM WD binaries continue to form and merge in both the disk and the halo.

  1. Advanced Thermal HPT Clearance Control

    NASA Technical Reports Server (NTRS)

    WojciechVoytek, Sak

    2006-01-01

    OBJECTIVE: Develop a fast acting HPT Active Clearance Control System to improve engine efficiency and reduce emissions CHALLENGE: Reduction of HPT blade clearance throughout engine operation System complexity, reliability and cost must remain comparable or surpass today s engines Reduced clearance may increase possibility of rubs

  2. Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity.

    PubMed

    Kudo-Saito, Chie; Fuwa, Takafumi; Kawakami, Yutaka

    2016-07-01

    Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM(+) cells including CD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derived suppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM(+) cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8(+) T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM(+) cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer. PMID:27208904

  3. Rapid blood clearance of biotinylated IgG after infusion of avidin

    SciTech Connect

    Sinitsyn, V.V.; Mamontova, A.G.; Checkneva, Y.Y.; Shnyra, A.A.; Domogatsky, S.P.

    1989-01-01

    The techniques of immunotherapy and radioimmunoimaging suffer from the problem of background: intravenously injected antibodies remain in the circulation much longer than it is necessary for effective binding to the target. Various approaches, including the postinjection of second antibodies, were explored to overcome the problem with some success. The phenomenon of a 100-fold more rapid blood clearance of biotinylated immunoglobulins after postinjection of an equivalent dose of avidin is described. The concentration of /sup 125/I-labeled biotinylated IgG in the circulation of rats slowly decreased to 20% of initial in 24 hr. Avidin injection at any interval during this period induced 90-95% reduction of radioactivity in blood in 15 min. Up to 70% of the radioactivity was recovered in the liver. Avidin-induced blood clearance of biotinylated immunoglobulins may find applications in immunotherapy and radio- or nuclear magnetic resonance immunoimaging.

  4. Development of tissue-targeting hemagglutinating virus of Japan envelope vector for successful delivery of therapeutic gene to mouse skin.

    PubMed

    Kawachi, Masako; Tamai, Katsuto; Saga, Kotaro; Yamazaki, Takehiko; Fujita, Hiroshi; Shimbo, Takashi; Kikuchi, Yasushi; Nimura, Keisuke; Nishifuji, Koji; Amagai, Masayuki; Uitto, Jouni; Kaneda, Yasufumi

    2007-10-01

    We report a novel strategy for constructing a tissue-targeting hemagglutinating virus of Japan (HVJ; Sendai virus) envelope vector (HVJ-E), and its application in gene therapy of a mouse model of genetic skin disease. Chimeric genes encoding viral F protein and green fluorescent protein (GFP) were constructed on the basis of various deletion mutants. The product of one chimeric gene, containing signal peptide, transmembrane domain, and the cytoplasmic tail of F protein, was transported to the cell surface and incorporated into new viruses released from HVJ-infected LLC-MK2 cells. For tissue targeting, in the preceding construct GFP was replaced with single-chain antibody (scFv) against mouse desmoglein 3 (mDsg3), a desmosomal cadherin found in basal layer keratinocytes of the skin. HVJ encoding scFv-F chimeric protein bound to mDsg3-coated plates much more efficiently than did wild-type HVJ. When chimeric HVJ was injected into a skin blister of a mouse model of epidermolysis bullosa, in which defective expression of type VII collagen results in a failure to secure epidermis to the underlying dermis, viral F protein expression was detected in most of the basal keratinocytes. Furthermore, chimeric HVJ-E introduced type VII collagen expression more efficiently compared with wild-type HVJ in basal keratinocytes of type VII collagen-deficient mouse skin, resulting in efficient amelioration of the genetic defect. Thus, a novel tissue-targeting HVJ-E could be used to successfully target epidermal keratinocytes both in vitro and in vivo. PMID:17892442

  5. Site clearance working group

    SciTech Connect

    1997-03-01

    The Gulf of Mexico and Louisiana continue to be areas with a high level of facility removal, and the pace of removal is projected to increase. Regulations were promulgated for the Gulf of Mexico and Louisiana requiring that abandoned sites be cleared of debris that could interfere with fishing and shrimping activities. The site clearance regulations also required verification that the sites were clear. Additionally, government programs were established to compensate fishermen for losses associated with snagging their equipment on oil and gas related objects that remained on the water bottoms in areas other than active producing sites and sites that had been verified as clear of obstructions and snags. The oil and gas industry funds the compensation programs. This paper reviews the regulations and evolving operating practices in the Gulf of Mexico and Louisiana where site clearance and fisherman`s gear compensation regulations have been in place for a number of years. Although regulations and guidelines may be in place elsewhere in the world, this paper focuses on the Gulf of Mexico and Louisiana. Workshop participants are encouraged to bring up international issues during the course of the workshop. Additionally, this paper raises questions and focuses on issues that are of concern to the various Gulf of Mexico and Louisiana water surface and water bottom stakeholders. This paper does not have answers to the questions or issues. During the workshop participants will debate the questions and issues in an attempt to develop consensus opinions and/or make suggestions that can be provided to the appropriate organizations, both private and government, for possible future research or policy adjustments. Site clearance and facility removal are different activities. Facility removal deals with removal of the structures used to produce oil and gas including platforms, wells, casing, piles, pipelines, well protection structures, etc.

  6. Toward a Fast-Response Active Turbine Tip Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.; Kypuros, Javier A.

    2003-01-01

    This paper describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, technologies developed for clearance control can benefit a broad spectrum of current and future turbomachinery. The first portion of the paper addresses the research from a programmatic viewpoint. Recent studies that provide motivation for the work, identification of key technologies, and NASA's plan for addressing deficiencies in the technologies are discussed. The later portion of the paper drills down into one of the key technologies by presenting equations and results for a preliminary dynamic model of the tip clearance phenomena.

  7. Parallel computation safety analysis irradiation targets fission product molybdenum in neutronic aspect using the successive over-relaxation algorithm

    NASA Astrophysics Data System (ADS)

    Susmikanti, Mike; Dewayatna, Winter; Sulistyo, Yos

    2014-09-01

    One of the research activities in support of commercial radioisotope production program is a safety research on target FPM (Fission Product Molybdenum) irradiation. FPM targets form a tube made of stainless steel which contains nuclear-grade high-enrichment uranium. The FPM irradiation tube is intended to obtain fission products. Fission materials such as Mo99 used widely the form of kits in the medical world. The neutronics problem is solved using first-order perturbation theory derived from the diffusion equation for four groups. In contrast, Mo isotopes have longer half-lives, about 3 days (66 hours), so the delivery of radioisotopes to consumer centers and storage is possible though still limited. The production of this isotope potentially gives significant economic value. The criticality and flux in multigroup diffusion model was calculated for various irradiation positions and uranium contents. This model involves complex computation, with large and sparse matrix system. Several parallel algorithms have been developed for the sparse and large matrix solution. In this paper, a successive over-relaxation (SOR) algorithm was implemented for the calculation of reactivity coefficients which can be done in parallel. Previous works performed reactivity calculations serially with Gauss-Seidel iteratives. The parallel method can be used to solve multigroup diffusion equation system and calculate the criticality and reactivity coefficients. In this research a computer code was developed to exploit parallel processing to perform reactivity calculations which were to be used in safety analysis. The parallel processing in the multicore computer system allows the calculation to be performed more quickly. This code was applied for the safety limits calculation of irradiated FPM targets containing highly enriched uranium. The results of calculations neutron show that for uranium contents of 1.7676 g and 6.1866 g (× 106 cm-1) in a tube, their delta reactivities are the still

  8. Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells

    PubMed Central

    2014-01-01

    Background The development of immunotherapy has led to significant progress in the treatment of metastatic cancer, including the development of genetic engineering technologies that redirect lymphocytes to recognize and target a wide variety of tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked to T cell signaling elements. Clinical trials of CAR-transduced peripheral blood lymphocytes (PBL) have induced remission of both solid organ and hematologic malignancies. Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target antigen that is overexpressed in multiple cancer histologies including melanoma, triple-negative breast cancer, glioblastoma, mesothelioma and sarcoma. Methods CSPG4 expression in cancer cell lines was assayed using flow cytometry (FACS) and reverse-transcription PCR (RT-PCR). Immunohistochemistry was utilized to assay resected melanomas and normal human tissues (n = 30) for CSPG4 expression and a reverse-phase protein array comprising 94 normal tissue samples was also interrogated for CSPG4 expression. CARs were successfully constructed from multiple murine antibodies (225.28S, TP41.2, 149.53) using second generation (CD28.CD3ζ) signaling domains. CAR sequences were cloned into a gamma-retroviral vector with subsequent successful production of retroviral supernatant and PBL transduction. CAR efficacy was assayed by cytokine release and cytolysis following coculture with target cell lines. Additionally, glioblastoma stem cells were generated from resected human tumors, and CSPG4 expression was determined by RT-PCR and FACS. Results Immunohistochemistry demonstrated prominent CSPG4 expression in melanoma tumors, but failed to demonstrate expression in any of the 30 normal human tissues studied. Two of 94 normal tissue protein lysates were positive by protein array. CAR constructs demonstrated cytokine secretion and cytolytic function after co-culture with tumor cell lines

  9. Mechanisms of viral clearance and persistence.

    PubMed

    Borrow, P

    1997-01-01

    Using examples predominantly drawn from study of the lymphocytic choriomeningitis virus (LCMV) model system, this review describes the mechanisms involved in control of virus infections by the cell-mediated immune response, and some of the different strategies viruses have evolved to evade such immune clearance so that they can persist in their hosts. The important role played by the CD8+ cytotoxic lymphocyte (CTL) response in clearance of many systemic virus infections is discussed; and it is emphasized that although CD8+ CTL are classically thought of as lymphocytes which mediate lysis of virus-infected target cells, the principal mechanism by which CD8+ T cells effect clearance of persistent and many acute virus infections via production of antiviral cytokines such as tumour necrosis factor-alpha and interferon-gamma, not via destruction of virus-producing cells. To avoid immune-mediated clearance, viruses frequently use a combination of several different strategies. These can be grouped into mechanisms for avoiding recognition by the immune response (such as establishing latent infections, replicating in immune-privileged sites, down-regulating the expression of immune recognition signals on the surface of infected cells, or undergoing antigenic variation); and mechanisms for suppressing the immune response. The latter include generalized immune suppression mechanisms, and strategies for more precisely disabling the specific immune response such as inducing tolerance or exhaustion of virus-specific CTL. The value of understanding both immune clearance mechanisms and viral evasion strategies in the rational design of immune-based therapies to combat persistent virus infections is discussed. PMID:9429206

  10. Turbomachinery Clearance Control

    NASA Technical Reports Server (NTRS)

    Chupp, Raymond E.; Hendricks, Robert C.; Lattime, Scott B.; Steinetz, Bruce M.; Aksit, Mahmut F.

    2007-01-01

    Controlling interface clearances is the most cost effective method of enhancing turbomachinery performance. Seals control turbomachinery leakages, coolant flows and contribute to overall system rotordynamic stability. In many instances, sealing interfaces and coatings are sacrificial, like lubricants, giving up their integrity for the benefit of the component. They are subjected to abrasion, erosion, oxidation, incursive rubs, foreign object damage (FOD) and deposits as well as extremes in thermal, mechanical, aerodynamic and impact loadings. Tribological pairing of materials control how well and how long these interfaces will be effective in controlling flow. A variety of seal types and materials are required to satisfy turbomachinery sealing demands. These seals must be properly designed to maintain the interface clearances. In some cases, this will mean machining adjacent surfaces, yet in many other applications, coatings are employed for optimum performance. Many seals are coating composites fabricated on superstructures or substrates that are coated with sacrificial materials which can be refurbished either in situ or by removal, stripping, recoating and replacing until substrate life is exceeded. For blade and knife tip sealing an important class of materials known as abradables permit blade or knife rubbing without significant damage or wear to the rotating element while maintaining an effective sealing interface. Most such tip interfaces are passive, yet some, as for the high-pressure turbine (HPT) case or shroud, are actively controlled. This work presents an overview of turbomachinery sealing. Areas covered include: characteristics of gas and steam turbine sealing applications and environments, benefits of sealing, types of standard static and dynamics seals, advanced seal designs, as well as life and limitations issues.

  11. Parallel computation safety analysis irradiation targets fission product molybdenum in neutronic aspect using the successive over-relaxation algorithm

    SciTech Connect

    Susmikanti, Mike; Dewayatna, Winter; Sulistyo, Yos

    2014-09-30

    One of the research activities in support of commercial radioisotope production program is a safety research on target FPM (Fission Product Molybdenum) irradiation. FPM targets form a tube made of stainless steel which contains nuclear-grade high-enrichment uranium. The FPM irradiation tube is intended to obtain fission products. Fission materials such as Mo{sup 99} used widely the form of kits in the medical world. The neutronics problem is solved using first-order perturbation theory derived from the diffusion equation for four groups. In contrast, Mo isotopes have longer half-lives, about 3 days (66 hours), so the delivery of radioisotopes to consumer centers and storage is possible though still limited. The production of this isotope potentially gives significant economic value. The criticality and flux in multigroup diffusion model was calculated for various irradiation positions and uranium contents. This model involves complex computation, with large and sparse matrix system. Several parallel algorithms have been developed for the sparse and large matrix solution. In this paper, a successive over-relaxation (SOR) algorithm was implemented for the calculation of reactivity coefficients which can be done in parallel. Previous works performed reactivity calculations serially with Gauss-Seidel iteratives. The parallel method can be used to solve multigroup diffusion equation system and calculate the criticality and reactivity coefficients. In this research a computer code was developed to exploit parallel processing to perform reactivity calculations which were to be used in safety analysis. The parallel processing in the multicore computer system allows the calculation to be performed more quickly. This code was applied for the safety limits calculation of irradiated FPM targets containing highly enriched uranium. The results of calculations neutron show that for uranium contents of 1.7676 g and 6.1866 g (× 10{sup 6} cm{sup −1}) in a tube, their delta

  12. Identifying Effective Enzyme Activity Targets for Recombinant Class I and Class II Collagenase for Successful Human Islet Isolation

    PubMed Central

    Balamurugan, Appakalai N.; Green, Michael L.; Breite, Andrew G.; Loganathan, Gopalakrishnan; Wilhelm, Joshua J.; Tweed, Benjamin; Vargova, Lenka; Lockridge, Amber; Kuriti, Manikya; Hughes, Michael G.; Williams, Stuart K.; Hering, Bernhard J.; Dwulet, Francis E.; McCarthy, Robert C.

    2016-01-01

    Background Isolation following a good manufacturing practice-compliant, human islet product requires development of a robust islet isolation procedure where effective limits of key reagents are known. The enzymes used for islet isolation are critical but little is known about the doses of class I and class II collagenase required for successful islet isolation. Methods We used a factorial approach to evaluate the effect of high and low target activities of recombinant class I (rC1) and class II (rC2) collagenase on human islet yield. Consequently, 4 different enzyme formulations with divergent C1:C2 collagenase mass ratios were assessed, each supplemented with the same dose of neutral protease. Both split pancreas and whole pancreas models were used to test enzyme targets (n = 20). Islet yield/g pancreas was compared with historical enzymes (n = 42). Results Varying the Wunsch (rC2) and collagen degradation activity (CDA, rC1) target dose, and consequently the C1:C2 mass ratio, had no significant effect on tissue digestion. Digestions using higher doses of Wunsch and CDA resulted in comparable islet yields to those obtained with 60% and 50% of those activities, respectively. Factorial analysis revealed no significant main effect of Wunsch activity or CDA for any parameter measured. Aggregate results from 4 different collagenase formulations gave 44% higher islet yield (>5000 islet equivalents/g) in the body/tail of the pancreas (n = 12) when compared with those from the same segment using a standard natural collagenase/protease mixture (n = 6). Additionally, islet yields greater than 5000 islet equivalents/g pancreas were also obtained in whole human pancreas. Conclusions A broader C1:C2 ratio can be used for human islet isolation than has been used in the past. Recombinant collagenase is an effective replacement for the natural enzyme and we have determined that high islet yield can be obtained even with low doses of rC1:rC2, which is beneficial for the survival

  13. Airway clearance in neuromuscular weakness.

    PubMed

    Gauld, Leanne Maree

    2009-05-01

    Impaired airway clearance leads to recurrent chest infections and respiratory deterioration in neuromuscular weakness. It is frequently the cause of death. Cough is the major mechanism of airway clearance. Cough has several components, and assessment tools are available to measure the different components of cough. These include measuring peak cough flow, respiratory muscle strength, and inspiratory capacity. Each is useful in assessing the ability to generate an effective cough, and can be used to guide when techniques of assisting airway clearance may be effective for the individual and which are most effective. Techniques to assist airway clearance include augmenting inspiration by air stacking, augmenting expiration by assisting the cough, and augmenting both inspiration and expiration with the mechanical insufflator-exsufflator or by direct suctioning via a tracheostomy. Physiotherapists are invaluable in assisting airway clearance, and in teaching patients and their families how to use these techniques. Use of the mechanical insufflator-exsufflator has gained popularity in recent times, but several simpler, more economical methods are available to assist airway clearance that can be used effectively alone or in combination. This review examines the literature available on the assessment and management of impaired airway clearance in neuromuscular weakness. PMID:19379290

  14. Dual clearance squeeze film damper

    NASA Technical Reports Server (NTRS)

    Fleming, D. P. (Inventor)

    1985-01-01

    A dual clearance hydrodynamic liquid squeeze film damper for a gas turbine engine is described. Under normal operating conditions, the device functions as a conventional squeeze film damper, using only one of its oil films. When an unbalance reaches abusive levels, as may occur with a blade loss or foreign object damage, a second, larger clearance film becomes active, controlling vibration amplitudes in a near optimum manner until the engine can be safely shut down and repaired.

  15. Method of mucociliary clearance assessment

    NASA Astrophysics Data System (ADS)

    Danilova, Tatiana V.; Manturov, Alexey O.; Ermakov, Igor Y.; Mareev, Gleb O.; Mareev, Oleg V.

    2016-04-01

    The article is devoted to the research capabilities of mucociliary clearance in the nasal cavity and paranasal sinuses using modern techniques of digital video recording and processing. We describe the setup and software for this method and the results of our research. Using microscope and digital camera we can provide a good method to study mucociliary clearance and by usage of special software we able to measure some characteristic of nasal mucosae and its main function.

  16. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

    PubMed

    Liu, Yu-Hui; Wang, Ye-Ran; Xiang, Yang; Zhou, Hua-Dong; Giunta, Brian; Mañucat-Tan, Noralyn B; Tan, Jun; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-02-01

    Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. PMID:24733588

  17. Success of the International Year of the Planet Earth through Targeted High-impact Programs at the American Geological Institute

    NASA Astrophysics Data System (ADS)

    Leahy, P.

    2007-12-01

    The American Geological Institute (AGI) is one of the 12 founding partners of the International Year of the Planet Earth (IYPE) and as such AGI serves on its governing board. AGI is a nonprofit federation of 44 geoscientific and professional associations that represents more than 120,000 geologists, geophysicists, and other earth scientists. AGI provides information services to geoscientists, serves as a voice of shared interests in our profession, plays a major role in strengthening geoscience education, and strives to increase public awareness of the vital role the geosciences play in society's use of resources, resilience to natural hazards, and the health of the environment. The outreach and educational opportunities afforded by IYPE provide AGI with an international venue to promote the role of the geosciences in the daily life of society. AGI's successful release of the 4-part television series entitled Faces of Earth done in partnership with the Discovery Communications is a hallmark example of an outreach product that is technically accurate but designed to engage the non-scientific audience in the wonderment of our science. The series focuses on building the planet, shaping the planet, assembling America, and the human world. Custom short cuts have been produced for special purposes and one of these may be used as part of an IYPE-launch event in Europe. AGI's news magazine, Geotimes will highlight appropriate IYPE events to increase the awareness of the American geoscience community. In addition, Geotimes will promote IYPE by using its logo routinely and through publishing advertisements reminding its professional and public readership of the importance of the IYPE triennium. Similarly, as part of AGI's K-12 educational efforts and teacher training and through its development of Earth Science Week materials, the goals, accomplishments, and importance of IYPE will be incorporated into the targeted educational audiences. IYPE activities will be highlighted

  18. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... takeoffs and landings. (c) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 23.239 can be shown with a lesser clearance. (d... airplane structure, plus any additional radial clearance necessary to prevent harmful vibration; (2)...

  19. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... takeoffs and landings. (c) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 23.239 can be shown with a lesser clearance. (d... airplane structure, plus any additional radial clearance necessary to prevent harmful vibration; (2)...

  20. 14 CFR 23.925 - Propeller clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... takeoffs and landings. (c) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 23.239 can be shown with a lesser clearance. (d... airplane structure, plus any additional radial clearance necessary to prevent harmful vibration; (2)...

  1. When "Becoming a 50% School" is Success Enough: A Principal-Agent Analysis of Subject Leaders' Target Setting

    ERIC Educational Resources Information Center

    Davies, Peter; Coates, Gwen; Hammersley-Fletcher, Linda; Mangan, Jean

    2005-01-01

    Using the perspective of principal-agent theory, we suggest that the target setting process imposed by the government has shifted teachers' focus away from their personal educational priorities. Our evidence suggests that schools with a higher proportion of students with high academic achievement differ in their practice of target setting from…

  2. Refrigeration system with clearance seals

    SciTech Connect

    Holland, N. J.

    1985-02-26

    In a refrigeration system such as a split Stirling system, fluid seals associated with the reciprocating displacer are virtually dragless clearance seals. Movement of the displacer relative to the pressure variations in the working volume of gas is retarded by a discrete braking element. Because it is not necessary that the brake providing any sealing action, the brake can be designed for greater durability and less dependence on ambient and operating temperatures. Similarly, the clearance seal can be formed of elements having low thermal expansion such that the seal is not temperature dependent. In the primary embodiments the braking element is a split friction brake.

  3. Inherited Disorders of Bilirubin Clearance

    PubMed Central

    Memon, Naureen; Weinberger, Barry I; Hegyi, Thomas; Aleksunes, Lauren M

    2016-01-01

    Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to bilirubin (e.g. Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), 3) bilirubin excretion into bile (Dubin-Johnson syndrome), or 4) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy. PMID:26595536

  4. Predictors of Success in Implementing HIV Prevention in Rural America: A State-Level Structural Factor Analysis of HIV Prevention Targeting Men who have Sex with Men

    PubMed Central

    Horvath, Keith J.

    2013-01-01

    Relatively few studies have examined the impact of modifying structural factors on HIV prevention efforts in the United States despite their high potential for lowering HIV prevalence rates. The aim of this study was to identify state-level characteristics of successful HIV prevention implementation. Structured interviews with 73 key informants in 13 rural states identified ‘more successful’ and ‘less successful’ states in HIV prevention. States were compared on demographic, religious, gay community, and funding variables. The 7 more successful states had both a wider variety and more MSM-targeted interventions. Overall funding, degree of epidemic, and “ruralness” were not significantly associated with success. Rather, successful states had less religious and Evangelical Protestant adherents and more ‘gay community’ infrastructure. They also spent a greater proportion of funds contracting community-based organizations and on MSMtargeted programming. Success in HIV prevention varies across rural states. Key demographic, social and economic indicators distinguish success in HIV prevention. PMID:17440806

  5. Contribution of renal and non-renal clearance on increased total clearance of adalimumab in glomerular disease.

    PubMed

    Roberts, Brittney V; Susano, Isidro; Gipson, Debbie S; Trachtman, Howard; Joy, Melanie S

    2013-09-01

    The contribution of renal and non-renal clearance toward targeted concentrations and/or effects of therapeutic proteins in nephrotic patients are unknown. This study dissected the contribution of clearance pathways to adalimumab elimination in patients with focal segmental glomerulosclerosis (FSGS). Urine was collected from seven patients treated with adalimumab. Renal clearance (ClR ) was measured and non-renal clearance (ClNR ) was calculated as the difference between total clearance and ClR . Differences in cumulative amount in urine, ClR, and ClNR between study weeks 1 and 16 and relationships between proteinuria (protein:creatinine ratio (Up/c)), and ClR and ClNR were evaluated. Up to 13% of the adalimumab dose was lost in urine. ClNR contributed more than ClR to enhanced total clearance. There was a nonlinear relationship between Up/c and ClR (R(2) 0.7059); an increase in ClR beginning at Up/c of 12 mg/mg [slope 1.755, (C.I. -7.825 to 11.34)]. There was a linear relationship between Up/c and ClNR (R(2) 0.5039); for every one unit increase in Up/c, ClNR would increase by 3.5 mL/hr (P = 0.01). Both ClR and ClNR contribute to enhanced total clearance of adalimumab in glomerular disease secondary to FSGS. Additional research is needed to identify mechanisms for the increased ClNR pathways. PMID:23813330

  6. Noninvasive clearance of airway secretions.

    PubMed

    Hardy, K A; Anderson, B D

    1996-06-01

    Airway clearance techniques are indicated for specific diseases that have known clearance abnormalities (Table 2). Murray and others have commented that such techniques are required only for patients with a daily sputum production of greater than 30 mL. The authors have observed that patients with diseases known to cause clearance abnormalities can have sputum clearance with some techniques, such as positive expiratory pressure, autogenic drainage, and active cycle of breathing techniques, when PDPV has not been effective. Hasani et al has shown that use of the forced exhalatory technique in patients with nonproductive cough still resulted in movement of secretions proximally from all regions of the lung in patients with airway obstruction. It is therefore reasonable to consider airway clearance techniques for any patient who has a disease known to alter mucous clearance, including CF, dyskinetic cilia syndromes, and bronchiectasis from any cause. Patients with atelectasis from mucous plugs and hypersecretory states, such as asthma and chronic bronchitis, patients with pain secondary to surgical procedures, and patients with neuromuscular disease, weak cough, and abnormal patency of the airway may also benefit from the application of airway clearance techniques. Infants and children up to 3 years of age with airway clearance problems need to be treated with PDPV. Manual percussion with hands alone or a flexible face mask or cup and small mechanical vibrator/percussors, such as the ultrasonic devices, can be used. The intrapulmonary percussive ventilator shows growing promise in this area. The high-frequency oscillator is not supplied with vests of appropriate sizes for tiny babies and has not been studied in this group. Young patients with neuromuscular disease may require assisted ventilation and airway oscillations can be applied. CPAP alone has been shown to improve achievable flow rates that will increase air-liquid interactions for patients with these diseases

  7. Targeted Exon Sequencing Successfully Discovers Rare Causative Genes and Clarifies the Molecular Epidemiology of Japanese Deafness Patients

    PubMed Central

    Kamatani, Naoyuki; Usami, Shin-ichi

    2013-01-01

    Target exon resequencing using Massively Parallel DNA Sequencing (MPS) is a new powerful strategy to discover causative genes in rare Mendelian disorders such as deafness. We attempted to identify genomic variations responsible for deafness by massive sequencing of the exons of 112 target candidate genes. By the analysis of 216randomly selected Japanese deafness patients (120 early-onset and 96 late-detected), who had already been evaluated for common genes/mutations by Invader assay and of which 48 had already been diagnosed, we efficiently identified causative mutations and/or mutation candidates in 57 genes. Approximately 86.6% (187/216) of the patients had at least one mutation. Of the 187 patients, in 69 the etiology of the hearing loss was completely explained. To determine which genes have the greatest impact on deafness etiology, the number of mutations was counted, showing that those in GJB2 were exceptionally higher, followed by mutations in SLC26A4, USH2A, GPR98, MYO15A, COL4A5 and CDH23. The present data suggested that targeted exon sequencing of selected genes using the MPS technology followed by the appropriate filtering algorithm will be able to identify rare responsible genes including new candidate genes for individual patients with deafness, and improve molecular diagnosis. In addition, using a large number of patients, the present study clarified the molecular epidemiology of deafness in Japanese. GJB2 is the most prevalent causative gene, and the major (commonly found) gene mutations cause 30–40% of deafness while the remainder of hearing loss is the result of various rare genes/mutations that have been difficult to diagnose by the conventional one-by-one approach. In conclusion, target exon resequencing using MPS technology is a suitable method to discover common and rare causative genes for a highly heterogeneous monogenic disease like hearing loss. PMID:23967202

  8. Microwave Blade Tip Clearance System: An Update

    NASA Technical Reports Server (NTRS)

    Geisheimer, Jon

    2006-01-01

    Newer engines use compressor bleed air and a model to close clearances open loop. Measuring clearances and closing the control loop can add additional efficiencies. Tip clearance control has been identified as a key technology for future engines Additional benefits in prognostics, NSMS, and condition-based maintenance. In the HPT for every 1 mil improvement in clearance: a) SFC decreases 0.1%; and b) EGT margin increases 1 C.

  9. The Dynamics of Apoptotic Cell Clearance.

    PubMed

    Elliott, Michael R; Ravichandran, Kodi S

    2016-07-25

    The phagocytic clearance of dying cells in a tissue is a highly orchestrated series of intercellular events coordinated by a complex signaling network. Recent data from genetic, biochemical, and live-imaging approaches have greatly enhanced our understanding of the dynamics of cell clearance and how the process is orchestrated at the cellular and tissue levels. We discuss how networks regulating apoptotic cell clearance are integrated to enable a rapid, efficient, and high-capacity clearance system within tissues. PMID:27459067

  10. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  11. 49 CFR 192.325 - Underground clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 3 2010-10-01 2010-10-01 false Underground clearance. 192.325 Section 192.325... Lines and Mains § 192.325 Underground clearance. (a) Each transmission line must be installed with at least 12 inches (305 millimeters) of clearance from any other underground structure not associated...

  12. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  13. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  14. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  15. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  16. 30 CFR 18.24 - Electrical clearances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Electrical clearances. 18.24 Section 18.24... APPROVAL OF MINING PRODUCTS ELECTRIC MOTOR-DRIVEN MINE EQUIPMENT AND ACCESSORIES Construction and Design Requirements § 18.24 Electrical clearances. Minimum clearances between uninsulated electrical...

  17. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall...

  18. 30 CFR 56.11010 - Stairstep clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Stairstep clearance. 56.11010 Section 56.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Travelways § 56.11010 Stairstep clearance. Vertical clearance...

  19. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 25.239(a) can be shown... to prevent harmful vibration; (2) At least one-half inch longitudinal clearance between the...

  20. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 25.239(a) can be shown... to prevent harmful vibration; (2) At least one-half inch longitudinal clearance between the...

  1. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of at least 18 inches between each propeller and the water, unless compliance with § 25.239(a) can be shown... to prevent harmful vibration; (2) At least one-half inch longitudinal clearance between the...

  2. 33 CFR 117.47 - Clearance gauges.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Clearance gauges. 117.47 Section 117.47 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.47 Clearance gauges. (a) Clearance gauges are required for drawbridges across navigable waters...

  3. 33 CFR 117.47 - Clearance gauges.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Clearance gauges. 117.47 Section 117.47 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.47 Clearance gauges. (a) Clearance gauges are required for drawbridges across navigable waters...

  4. 33 CFR 117.47 - Clearance gauges.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Clearance gauges. 117.47 Section 117.47 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.47 Clearance gauges. (a) Clearance gauges are required for drawbridges across navigable waters...

  5. 33 CFR 117.47 - Clearance gauges.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Clearance gauges. 117.47 Section 117.47 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.47 Clearance gauges. (a) Clearance gauges are required for drawbridges across navigable waters...

  6. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  7. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  8. 22 CFR 16.6 - Security clearances.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Security clearances. 16.6 Section 16.6 Foreign Relations DEPARTMENT OF STATE PERSONNEL FOREIGN SERVICE GRIEVANCE SYSTEM § 16.6 Security clearances. The agencies shall use their best endeavors to expedite security clearances whenever necessary to ensure a...

  9. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor... (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall be prominently posted where the height is insufficient for vehicles and equipment....

  10. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor... (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall be prominently posted where the height is insufficient for vehicles and equipment....

  11. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor... (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall be prominently posted where the height is insufficient for vehicles and equipment....

  12. 29 CFR 1917.113 - Clearance heights.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Clearance heights. 1917.113 Section 1917.113 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) MARINE TERMINALS Terminal Facilities § 1917.113 Clearance heights. Clearance heights shall...

  13. Removal - An alternative to clearance

    SciTech Connect

    Feinhals, J.; Kelch, A.; Kunze, V.

    2007-07-01

    This presentation shows the differences between the application of clearance and removal, both being procedures for materials leaving radiation protection areas permanently. The differentiation will be done on the basis of the German legislation but may be also applicable for other national legislation. For clearance in Germany two basic requirements must be given, i.e. that the materials are activated or contaminated and that they result from the licensed use or can be assigned to the scope of the license. Clearance needs not to be applied to objects in Germany which are to be removed only temporarily from controlled areas with the purpose of repair or reuse in other controlled areas. In these cases only the requirements of contamination control apply. In the case of removal it must either be proved by measurements that the relevant materials are neither activated nor contaminated or that the materials result from areas where activation or contamination is impossible due to the operational history considering operational procedures and events. If the material is considered neither activated nor contaminated there is no need for a clearance procedure. Therefore, these materials can be removed from radiation protection areas and the removal is in the responsibility of the licensee. Nevertheless, the removal procedure and the measuring techniques to be applied for the different types of materials need an agreement from the competent authority. In Germany a maximum value of 10% of the clearance values has been established in different licenses as a criterion for the application of removal. As approximately 2/3 of the total mass of a nuclear power plant is not expected to be contaminated or activated there is a need for such a procedure of removal for this non contaminated material without any regulatory control especially in the case of decommissioning. A remarkable example is NPP Stade where in the last three years more than 8600 Mg were disposed of by removal and

  14. Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

    PubMed

    Ellsworth, Bruce A; Sher, Philip M; Wu, Ximao; Wu, Gang; Sulsky, Richard B; Gu, Zhengxiang; Murugesan, Natesan; Zhu, Yeheng; Yu, Guixue; Sitkoff, Doree F; Carlson, Kenneth E; Kang, Liya; Yang, Yifan; Lee, Ning; Baska, Rose A; Keim, William J; Cullen, Mary Jane; Azzara, Anthony V; Zuvich, Eva; Thomas, Michael A; Rohrbach, Kenneth W; Devenny, James J; Godonis, Helen E; Harvey, Susan J; Murphy, Brian J; Everlof, Gerry G; Stetsko, Paul I; Gudmundsson, Olafur; Johnghar, Susan; Ranasinghe, Asoka; Behnia, Kamelia; Pelleymounter, Mary Ann; Ewing, William R

    2013-12-12

    Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile. PMID:24182233

  15. Prediction of drug clearance in children.

    PubMed

    Foissac, Frantz; Bouazza, Naïm; Valade, Elodie; De Sousa Mendes, Mailys; Fauchet, Floris; Benaboud, Sihem; Hirt, Déborah; Tréluyer, Jean-Marc; Urien, Saïk

    2015-07-01

    The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight-based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age-related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months-2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months. PMID:25721251

  16. Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoetic Cell Transplant Recipients.

    PubMed

    Navarro, Sandi L; Randolph, Timothy W; Shireman, Laura M; Raftery, Daniel; McCune, Jeannine S

    2016-08-01

    Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings. PMID:27350098

  17. The relevance of drug clearance to antibiotic dosing in critically ill patients.

    PubMed

    Roberts, Darren M

    2011-12-01

    To maximise the effect of an antibiotic it is necessary to pay careful attention to dosing. The maintenance dose is determined by antibiotic clearance which is usually determined in young healthy adults with normal physiology. Antibiotic clearance in critically ill patients may increase or decrease due to altered physiology and the treatments that are administered. Clearance may also vary significantly over time in patients with critical illness. Advancing age and comorbidities, in particular chronic kidney disease, can also decrease antibiotic clearance. Therefore, it is complicated and arguably impossible to suggest generic guidelines for the dosing of antibiotics in critically ill patients. Factors that influence clearance must be identified and accounted for in each patient for a rational approach to dose adjustment of antibiotics in patients with critical illness. The necessary changes can be predicted by understanding pharmacokinetic concepts. It is necessary to quantify organ function in patients at multiple time points because this can be used to estimate antibiotic clearance and guide dose selection. For example, creatinine clearance should be calculated but methods used in ambulatory patients may not apply to patients with critical illness. If possible, therapeutic drug monitoring should be conducted to ensure that antibiotic concentration targets are achieved and also to guide titration of subsequent doses. If blood sampling is carefully planned it may be possible to directly measure antibiotic clearance for dose adjustment. The purpose of this article is to review the concept of clearance and to highlight circumstances where antibiotic clearance may be altered in patients with critical illness. Strategies for dose modification of antibiotics in critically ill patients will be discussed. PMID:21554217

  18. Impairment of paravascular clearance pathways in the aging brain

    PubMed Central

    Kress, Benjamin T.; Iliff, Jeffrey J.; Xia, Maosheng; Wang, Minghuan; Wei, Helen; Zeppenfeld, Douglas; Xie, Lulu; Kang, Hongyi; Xu, Qiwu; Liew, Jason; Plog, Benjamin A.; Ding, Fengfei; Deane, Rashid; Nedergaard, Maiken

    2014-01-01

    Objective In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal and interstitial fluids. Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular cerebrospinal fluid (CSF) pathways. The Objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. Methods CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy while interstitial solute clearance was evaluated by radio-tracer clearance assays in young (2–3 month), middle age (10–12 month) and old (18–20 month) wild type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function were evaluated by immunofluorescence. Results Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparechamally injected amyloid β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. Interpretation We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of mis-folded protein aggregates. PMID:25204284

  19. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

    PubMed Central

    Gomez-Sanchez, Jose A.; Carty, Lucy; Iruarrizaga-Lejarreta, Marta; Palomo-Irigoyen, Marta; Varela-Rey, Marta; Griffith, Megan; Hantke, Janina; Macias-Camara, Nuria; Azkargorta, Mikel; Aurrekoetxea, Igor; De Juan, Virginia Gutiérrez; Jefferies, Harold B.J.; Aspichueta, Patricia; Elortza, Félix; Aransay, Ana M.; Martínez-Chantar, María L.; Baas, Frank; Mato, José M.; Mirsky, Rhona

    2015-01-01

    Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell–mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury. We also present evidence that myelinophagy is defective in the injured central nervous system. These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease. PMID:26150392

  20. AHERA CLEARANCE AT TWENTY ABATEMENT SITES

    EPA Science Inventory

    A study was conducted during the summer of 1988 to document Asbestos Hazard Emergency Response Act (AHERA) clearance air sampling practices and clearance concentrations of airborne asbestos at 20 asbestos-abatement sites in New Jersey. ach abatement took place in a school buildin...

  1. AHERA CLEARANCE AT TWENTY ABATEMENT SITES

    EPA Science Inventory

    A study was conducted during the summer of 1988 to document Asbestos Hazard Emergency Response Act (AHERA) clearance air-sampling practices and clearance concentrations of airborne asbestos at 20 asbestos-abatement sites in New Jersey. Each abatement took place in a school buildi...

  2. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or taxiing... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of...

  3. 14 CFR 25.925 - Propeller clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... nose wheel landing gear) or nine inches (for each airplane with tail wheel landing gear) between each propeller and the ground with the landing gear statically deflected and in the level takeoff, or taxiing... the corresponding landing gear strut bottomed. (b) Water clearance. There must be a clearance of...

  4. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Manifest Requirements for Passengers, Crew Members, and Non-Crew Members Onboard Commercial Aircraft Departing From the United States § 122.77 Clearance certificate. (a) Aircraft departing from the U.S. One... director to show that clearance is granted. (b) Scheduled aircraft. If a scheduled aircraft clears at...

  5. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Manifest Requirements for Passengers, Crew Members, and Non-Crew Members Onboard Commercial Aircraft Departing From the United States § 122.77 Clearance certificate. (a) Aircraft departing from the U.S. One... director to show that clearance is granted. (b) Scheduled aircraft. If a scheduled aircraft clears at...

  6. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Manifest Requirements for Passengers, Crew Members, and Non-Crew Members Onboard Commercial Aircraft Departing From the United States § 122.77 Clearance certificate. (a) Aircraft departing from the U.S. One... director to show that clearance is granted. (b) Scheduled aircraft. If a scheduled aircraft clears at...

  7. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Manifest Requirements for Passengers, Crew Members, and Non-Crew Members Onboard Commercial Aircraft Departing From the United States § 122.77 Clearance certificate. (a) Aircraft departing from the U.S. One... director to show that clearance is granted. (b) Scheduled aircraft. If a scheduled aircraft clears at...

  8. 30 CFR 56.11008 - Restricted clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 56.11008 Section 56.11008 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Travelways § 56.11008 Restricted clearance. Where...

  9. 49 CFR 192.325 - Underground clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Lines and Mains § 192.325 Underground clearance. (a) Each transmission line must be installed with at... the transmission line. If this clearance cannot be attained, the transmission line must be protected... the requirements of paragraph (a) or (b) of this section, each plastic transmission line or main...

  10. 49 CFR 192.325 - Underground clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Lines and Mains § 192.325 Underground clearance. (a) Each transmission line must be installed with at... the transmission line. If this clearance cannot be attained, the transmission line must be protected... the requirements of paragraph (a) or (b) of this section, each plastic transmission line or main...

  11. 49 CFR 192.325 - Underground clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Lines and Mains § 192.325 Underground clearance. (a) Each transmission line must be installed with at... the transmission line. If this clearance cannot be attained, the transmission line must be protected... the requirements of paragraph (a) or (b) of this section, each plastic transmission line or main...

  12. 24 CFR 35.1340 - Clearance.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... abatement of lead-based paint or lead-based paint hazards shall be performed in accordance with 40 CFR 745... the steps set forth at 40 CFR 745.227(e)(8). If clearance is being performed after lead-based paint... certified to perform risk assessments or lead-based paint inspections. (b) Clearance following...

  13. 24 CFR 35.1340 - Clearance.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... abatement of lead-based paint or lead-based paint hazards shall be performed in accordance with 40 CFR 745... the steps set forth at 40 CFR 745.227(e)(8). If clearance is being performed after lead-based paint... certified to perform risk assessments or lead-based paint inspections. (b) Clearance following...

  14. 24 CFR 35.1340 - Clearance.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... abatement of lead-based paint or lead-based paint hazards shall be performed in accordance with 40 CFR 745... the steps set forth at 40 CFR 745.227(e)(8). If clearance is being performed after lead-based paint... certified to perform risk assessments or lead-based paint inspections. (b) Clearance following...

  15. 24 CFR 35.1340 - Clearance.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... abatement of lead-based paint or lead-based paint hazards shall be performed in accordance with 40 CFR 745... the steps set forth at 40 CFR 745.227(e)(8). If clearance is being performed after lead-based paint... certified to perform risk assessments or lead-based paint inspections. (b) Clearance following...

  16. 19 CFR 122.77 - Clearance certificate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Clearance certificate. 122.77 Section 122.77 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Documents Required for Clearance and Permission To Depart;...

  17. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  18. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  19. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  20. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  1. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  2. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  3. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  4. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  5. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  6. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  7. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  8. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  9. 30 CFR 57.7028 - Hand clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Hand clearance. 57.7028 Section 57.7028 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND... Drilling-Underground Only § 57.7028 Hand clearance. Persons shall not rest their hands on the chuck...

  10. 30 CFR 57.7018 - Hand clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Hand clearance. 57.7018 Section 57.7018 Mineral... Drilling-Surface Only § 57.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling. Drilling—Underground Only...

  11. 30 CFR 56.7018 - Hand clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Hand clearance. 56.7018 Section 56.7018 Mineral... Drilling § 56.7018 Hand clearance. Persons shall not hold the drill steel while collaring holes, or rest their hands on the chuck or centralizer while drilling....

  12. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... be processed for a security clearance in accordance with 32 CFR part 353 and the provisions of this... shall be accomplished in accordance with 32 CFR part 159. The investigative requirement shall be the... 32 National Defense 1 2014-07-01 2014-07-01 false Security clearance. 154.16 Section...

  13. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... be processed for a security clearance in accordance with 32 CFR part 353 and the provisions of this... shall be accomplished in accordance with 32 CFR part 159. The investigative requirement shall be the... 32 National Defense 1 2010-07-01 2010-07-01 false Security clearance. 154.16 Section...

  14. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... be processed for a security clearance in accordance with 32 CFR part 353 and the provisions of this... shall be accomplished in accordance with 32 CFR part 159. The investigative requirement shall be the... 32 National Defense 1 2012-07-01 2012-07-01 false Security clearance. 154.16 Section...

  15. Intelligent Engine Systems: HPT Clearance Control

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Advanced Thermally Actuated Clearance Control System underwent several studies. Improved flow path isolation quantified what can be gained by making the HPT case nearly adiabatic. The best method of heat transfer was established, and finally two different borrowed air cooling circuits were evaluated to be used for the HPT Active Clearance Control System.

  16. Ginsenoside compound K promotes β-amyloid peptide clearance in primary astrocytes via autophagy enhancement.

    PubMed

    Guo, Jinhui; Chang, Li; Zhang, Xin; Pei, Sujuan; Yu, Meishuang; Gao, Jianlian

    2014-10-01

    The aim of the present study was to investigate the effect of ginsenoside compound K on β-amyloid (Aβ) peptide clearance in primary astrocytes. Aβ degradation in primary astrocytes was determined using an intracellular Aβ clearance assay. Aggregated LC3 in astrocyte cells, which is a marker for the level of autophagy, was detected using laser scanning confocal microscope. The effect of compound K on the mammalian target of rapamycin (mTOR)/autophagy pathway was determined using western blot analysis, and an enzyme-linked immunosorbent assay was used for Aβ detection. The results demonstrated that compound K promoted the clearance of Aβ and enhanced autophagy in primary astrocytes. In addition, it was found that phosphorylation of mTOR was inhibited by compound K, which may have contributed to the enhanced autophagy. In conclusion, compound K promotes Aβ clearance by enhancing autophagy via the mTOR signaling pathway in primary astrocytes. PMID:25187838

  17. Design of ligand-targeted nanoparticles for enhanced cancer targeting

    NASA Astrophysics Data System (ADS)

    Stefanick, Jared F.

    Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted

  18. Xenon spill distribution and room clearance.

    PubMed

    Kelsey, C A; Telepak, R J

    1999-11-01

    The purpose of these studies was to investigate actual xenon gas clearance times under different exhaust conditions, to compare them with the calculated clearance times, to observe the distribution of the xenon gas while it was being exhausted from the room, and to determine the cause of a stationary xenon cloud that appeared on some clinical images. Clearance times with and without a flexible exhaust hose placed next to a simulated 133Xe gas spill were compared with clearance times measured in a room with all exhaust closed off. Two gamma cameras were used to observe the transport and exhaust of xenon following a simulated spill. Clearance times with the flexible exhaust hose were less than one minute because the xenon gas was removed before it had a chance to disperse into the room. Conventional room clearance calculations based on uniform mixing and measured exhaust rates yielded a clearance time of 22 min. The source of an artifactual stationary cloud image was discovered to be a small amount of xenon trapped between the collimator and camera face. A negative pressure and dedicated exhaust can be even more effective in exhausting spilled xenon from a room than air transfer calculations predict. The authors believe the flexible hose should always be used. PMID:10524516

  19. Advanced optical blade tip clearance measurement system

    NASA Technical Reports Server (NTRS)

    Ford, M. J.; Honeycutt, R. E.; Nordlund, R. E.; Robinson, W. W.

    1978-01-01

    An advanced electro-optical system was developed to measure single blade tip clearances and average blade tip clearances between a rotor and its gas path seal in an operating gas turbine engine. This system is applicable to fan, compressor, and turbine blade tip clearance measurement requirements, and the system probe is particularly suitable for operation in the extreme turbine environment. A study of optical properties of blade tips was conducted to establish measurement system application limitations. A series of laboratory tests was conducted to determine the measurement system's operational performance characteristics and to demonstrate system capability under simulated operating gas turbine environmental conditions. Operational and environmental performance test data are presented.

  20. Comparison of Two Alternate Methods for Tracking Toe Clearance

    NASA Technical Reports Server (NTRS)

    Miller, Christopher A.; Feiveson, Alan H.; Bloomberg, Jacob J.

    2007-01-01

    Analyses of toe clearance during the swing phase of locomotion has often been utilized in determining a subject s propensity to trip while either walking or stepping over an obstacle. In the literature, toe clearance has been studied using a marker on the superior aspect of the second toe (rtoe), a marker on the lateral aspect of the fifth metatarsal head (mth5), or a virtual marker positioned at the anterior tip of the toe (vtoe). The purpose of this study was to compute toe clearance and associated parameters using a fifth metatarsal marker and a virtual toe marker, and compare the results with those of the standard toe marker. Subjects walked on a motorized treadmill at five different speeds while performing a visual acuity task at two separate target distances (ten 60-second trials). The minimum vertical height (TCl) was determined for each stride, along with its point of occurence in the gait cycle, and the angles of the foot and ankle at that time. A regression analysis was performed on the vtoe and mth5 results versus rtoe individually. For all TCl parameters, the mth5 marker did not correlate well with rtoe; the vtoe marker showed better agreement. Most importantly, the mth5 marker predicted a later occurence of TCl than rtoe and vtoe - thereby missing the most dangerous point in swing phase for a trip. From this analysis, the vtoe marker proved to be a better analog to rtoe than mth5, especially for determining a subject s propensity to trip.

  1. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

    PubMed Central

    Reddy, Kavya; Cusack, Corey L.; Nnah, Israel C.; Khayati, Khoosheh; Saqcena, Chaitali; Huynh, Tuong B.; Noggle, Scott A.; Ballabio, Andrea; Dobrowolski, Radek

    2016-01-01

    Summary Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD. PMID:26923592

  2. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.

    PubMed

    Reddy, Kavya; Cusack, Corey L; Nnah, Israel C; Khayati, Khoosheh; Saqcena, Chaitali; Huynh, Tuong B; Noggle, Scott A; Ballabio, Andrea; Dobrowolski, Radek

    2016-03-01

    Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD. PMID:26923592

  3. RAB24 facilitates clearance of autophagic compartments during basal conditions

    PubMed Central

    Ylä-Anttila, Päivi; Mikkonen, Elisa; Happonen, Kaisa E; Holland, Petter; Ueno, Takashi; Simonsen, Anne; Eskelinen, Eeva-Liisa

    2015-01-01

    RAB24 belongs to a family of small GTPases and has been implicated to function in autophagy. Here we confirm the intracellular localization of RAB24 to autophagic vacuoles with immuno electron microscopy and cell fractionation, and show that prenylation and guanine nucleotide binding are necessary for the targeting of RAB24 to autophagic compartments. Further, we show that RAB24 plays a role in the maturation and/or clearance of autophagic compartments under nutrient-rich conditions, but not during short amino acid starvation. Quantitative electron microscopy shows an increase in the numbers of late autophagic compartments in cells silenced for RAB24, and mRFP-GFP-LC3 probe and autophagy flux experiments indicate that this is due to a hindrance in their clearance. Formation of autophagosomes is shown to be unaffected by RAB24-silencing with siRNA. A defect in aggregate clearance in the absence of RAB24 is also shown in cells forming polyglutamine aggregates. This study places RAB24 function in the termination of the autophagic process under nutrient-rich conditions. PMID:26325487

  4. Nucleotide-mediated airway clearance.

    PubMed

    Schmid, Andreas; Clunes, Lucy A; Salathe, Mathias; Verdugo, Pedro; Dietl, Paul; Davis, C William; Tarran, Robert

    2011-01-01

    A thin layer of airway surface liquid (ASL) lines the entire surface of the lung and is the first point of contact between the lung and the environment. Surfactants contained within this layer are secreted in the alveolar region and are required to maintain a low surface tension and to prevent alveolar collapse. Mucins are secreted into the ASL throughout the respiratory tract and serve to intercept inhaled pathogens, allergens and toxins. Their removal by mucociliary clearance (MCC) is facilitated by cilia beating and hydration of the ASL by active ion transport. Throughout the lung, secretion, ion transport and cilia beating are under purinergic control. Pulmonary epithelia release ATP into the ASL which acts in an autocrine fashion on P2Y(2) (ATP) receptors. The enzymatic network describes in Chap. 2 then mounts a secondary wave of signaling by surface conversion of ATP into adenosine (ADO), which induces A(2B) (ADO) receptor-mediated responses. This chapter offers a comprehensive description of MCC and the extensive ramifications of the purinergic signaling network on pulmonary surfaces. PMID:21560046

  5. Plasma Creatinine Clearance in the Dog

    ERIC Educational Resources Information Center

    Frazier, Loy W.

    1977-01-01

    Lists materials and methods for an experiment that demonstrates the concept of glomerular filtration rate (GFR) using anesthesized dogs. In the dog, GFR is equivalent to the renal plasma clearance of exogenous creatinine. (CS)

  6. Shear joint capability versus bolt clearance

    NASA Technical Reports Server (NTRS)

    Lee, H. M.

    1992-01-01

    The results of a conservative analysis approach into the determination of shear joint strength capability for typical space-flight hardware as a function of the bolt-hole clearance specified in the design are presented. These joints are comprised of high-strength steel fasteners and abutments constructed of aluminum alloys familiar to the aerospace industry. A general analytical expression was first arrived at which relates bolt-hole clearance to the bolt shear load required to place all joint fasteners into a shear transferring position. Extension of this work allowed the analytical development of joint load capability as a function of the number of fasteners, shear strength of the bolt, bolt-hole clearance, and the desired factor of safety. Analysis results clearly indicate that a typical space-flight hardware joint can withstand significant loading when less than ideal bolt hole clearances are used in the design.

  7. Shear-Joint Capability Versus Bolt Clearance

    NASA Technical Reports Server (NTRS)

    Lee, H. M.

    1994-01-01

    NASA Technical Memorandum presents theoretical study of relationships between load-bearing capabilities of shear joints that comprise plates clamped together by multiple bolts and clearances between bolts and boltholes in those joints.

  8. Voltage-clearance recommendations for printed boards

    SciTech Connect

    Jennings, C W; Cave, G; Evans, A; Harrington, D J; Kirchenbaum, J; Martz, R E; Mierendorf, R C; Smith, G A

    1980-01-01

    Present and future trends in printed board designs point to higher circuit densities with narrower lines and closer spacings. Some designers are now laying out boards with 0.13 mm lines and spacings. The reduction of nominal spacing between conductive elements has raised questions concerning the adequacy of present voltage-clearance recommendations. The present recommendations are considered too conservative in that they are weighted with large safety factors, especially for small clearances, and are frequently disregarded by many designers. Published voltage breakdown measurements made on printed boards with comb patterns with their enhanced conductor test lengths show breakdowns occurring at much higher voltages than those specified for the clearances in existing documents. A Task Group was set up to review published breakdown measurements and to make any additional measurements necessary to provide voltage-clearance recommendations. These recommendations are reported.

  9. Compressor airfoil tip clearance optimization system

    SciTech Connect

    Little, David A.; Pu, Zhengxiang

    2015-08-18

    A compressor airfoil tip clearance optimization system for reducing a gap between a tip of a compressor airfoil and a radially adjacent component of a turbine engine is disclosed. The turbine engine may include ID and OD flowpath boundaries configured to minimize compressor airfoil tip clearances during turbine engine operation in cooperation with one or more clearance reduction systems that are configured to move the rotor assembly axially to reduce tip clearance. The configurations of the ID and OD flowpath boundaries enhance the effectiveness of the axial movement of the rotor assembly, which includes movement of the ID flowpath boundary. During operation of the turbine engine, the rotor assembly may be moved axially to increase the efficiency of the turbine engine.

  10. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms

    PubMed Central

    Mansilla Pareja, Maria Eugenia; Colombo, Maria I.

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance. PMID:24137567

  11. Year in review 2014: airway clearance.

    PubMed

    Strickland, Shawna L

    2015-04-01

    The respiratory therapist has had integrated adjuncts to improve mucus clearance for decades. However, there is a lack of literature describing the impact of these interventions on specific patient populations, resulting in an inability to make recommendations about the use of devices and techniques. The purpose of this article is to review recent literature regarding airway clearance therapies in a manner that is most likely to have interest to the readers of Respiratory Care. PMID:25784773

  12. Visualization of viral clearance in the living animal

    SciTech Connect

    Verdin, E.M.; Maratos-Flier, E.; Kahn, C.R.; Sodoyez, J.C.; Sodoyez-Goffaux, F.; De Vos, C.J.; Lynn, S.P.; Fields, B.N.

    1987-04-24

    The early events in viral dissemination via the bloodstream were identified by monitoring the fate of /sup 123/I-radiolabeled reovirus after it was injected intravenously in rats. Continuous scintillation camera imaging showed that reovirus serotypes 1 and 3 were cleared from the circulation in less than 10 minutes by specific and distinct target organs. Reovirus serotype 1 accumulated predominantly in the lungs and the liver, whereas serotype 3 accumulated in the liver and the spleen with very little virus uptake by the lungs. Incubation of reovirus serotype 1 with a monoclonal antibody directed against the viral hemagglutinin before injection totally inhibited the clearance of the virus by the lungs. Similar results were obtained when viruses biolabeled with /sup 35/S were used. These results demonstrate that viruses can be rapidly transported through the bloodstream to specific target organs and that the localization of the viruses depends on the interaction between specific viral surface components and the target organ.

  13. ADAPTIVE CLEARANCE CONTROL SYSTEMS FOR TURBINE ENGINES

    NASA Technical Reports Server (NTRS)

    Blackwell, Keith M.

    2004-01-01

    The Controls and Dynamics Technology Branch at NASA Glenn Research Center primarily deals in developing controls, dynamic models, and health management technologies for air and space propulsion systems. During the summer of 2004 I was granted the privilege of working alongside professionals who were developing an active clearance control system for commercial jet engines. Clearance, the gap between the turbine blade tip and the encompassing shroud, increases as a result of wear mechanisms and rubbing of the turbine blades on shroud. Increases in clearance cause larger specific fuel consumption (SFC) and loss of efficient air flow. This occurs because, as clearances increase, the engine must run hotter and bum more fuel to achieve the same thrust. In order to maintain efficiency, reduce fuel bum, and reduce exhaust gas temperature (EGT), the clearance must be accurately controlled to gap sizes no greater than a few hundredths of an inch. To address this problem, NASA Glenn researchers have developed a basic control system with actuators and sensors on each section of the shroud. Instead of having a large uniform metal casing, there would be sections of the shroud with individual sensors attached internally that would move slightly to reform and maintain clearance. The proposed method would ultimately save the airline industry millions of dollars.

  14. Protein Clearance Mechanisms of Alpha-Synuclein and Amyloid-Beta in Lewy Body Disorders

    PubMed Central

    Deleidi, Michela; Maetzler, Walter

    2012-01-01

    Protein clearance is critical for the maintenance of the integrity of neuronal cells, and there is accumulating evidence that in most—if not all—neurodegenerative disorders, impaired protein clearance fundamentally contributes to functional and structural alterations eventually leading to clinical symptoms. Dysfunction of protein clearance leads to intra- and extraneuronal accumulation of misfolded proteins and aggregates. The pathological hallmark of Lewy body disorders (LBDs) is the abnormal accumulation of misfolded proteins such as alpha-synuclein (Asyn) and amyloid-beta (Abeta) in a specific subset of neurons, which in turn has been related to deficits in protein clearance. In this paper we will highlight common intraneuronal (including autophagy and unfolded protein stress response) and extraneuronal (including interaction of neurons with astrocytes and microglia, phagocytic clearance, autoimmunity, cerebrospinal fluid transport, and transport across the blood-brain barrier) protein clearance mechanisms, which may be altered across the spectrum of LBDs. A better understanding of the pathways underlying protein clearance—in particular of Asyn and Abeta—in LBDs may result in the identification of novel biomarkers for disease onset and progression and of new therapeutic targets. PMID:23133788

  15. The Aβ-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain.

    PubMed

    Kerridge, Caroline; Belyaev, Nikolai D; Nalivaeva, Natalia N; Turner, Anthony J

    2014-08-01

    Proteolytic cleavage of the amyloid precursor protein (APP) by the successive actions of β- and γ-secretases generates several biologically active metabolites including the amyloid β-peptide (Aβ) and the APP intracellular domain (AICD). By analogy with the Notch signalling pathway, AICD has been proposed to play a role in transcriptional regulation. Among the cohort of genes regulated by AICD is the Aβ-degrading enzyme neprilysin (NEP). AICD binds to the NEP promoter causing transcriptional activation by competitive replacement with histone deacetylases (HDACs) leading to increased levels of NEP activity and hence increased Aβ clearance. We now show that the Aβ-clearance protein transthyretin (TTR) is also epigenetically up-regulated by AICD. Like NEP regulation, AICD derived specifically from the neuronal APP isoform, APP695 , binds directly to the TTR promoter displacing HDAC1 and HDAC3. Cell treatment with the tyrosine kinase inhibitor Gleevec (imatinib) or with the alkalizing agent NH4 Cl causes an accumulation of 'functional' AICD capable of up-regulating both TTR and NEP, leading to a reduction in total cellular Aβ levels. Pharmacological regulation of both NEP and TTR might represent a viable therapeutic target in Alzheimer's disease. PMID:24528201

  16. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  17. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  18. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  19. 19 CFR 4.61 - Requirements for clearance.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Requirements for clearance. 4.61 Section 4.61 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY VESSELS IN FOREIGN AND DOMESTIC TRADES Foreign Clearances § 4.61 Requirements for clearance. (a) Application for clearance. A...

  20. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Plant clearance function... Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency, the contracting officer shall assume all responsibilities of the plant clearance...

  1. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Plant clearance function... Plant clearance function. If the plant clearance function has not been formally delegated to another Federal agency, the contracting officer shall assume all responsibilities of the plant clearance...

  2. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Business clearance review... Authority, and Responsibilities 801.602-76 Business clearance review. (a) A business clearance review is a... obtain a business clearance review prior to award of any contract, task or delivery order, or...

  3. Reduction in C-reactive protein indicates successful targeting of the IL-1/IL-6 axis resulting in improved survival in early stage multiple myeloma.

    PubMed

    Lust, John A; Lacy, Martha Q; Zeldenrust, Steven R; Witzig, Thomas E; Moon-Tasson, Laurie L; Dinarello, Charles A; Donovan, Kathleen A

    2016-06-01

    We report the long-term follow-up results of a phase II trial of IL-1 receptor antagonist and low-dose dexamethasone for early stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent multiple myeloma (IMM) without the need for immediate therapy. Forty seven patients were enrolled and subsequently treated with IL-1Ra; in 25/47 low-dose dexamethasone (20 mg weekly) was added. The primary endpoint was progression-free survival (PFS). In the clinical trial, three patients achieved a minor response (MR) to IL-1Ra alone; five patients a partial response (PR) and four patients an MR after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index (PCLI) which paralleled a decrease in the high sensitivity C-reactive protein (hs-CRP). The median PFS for the 47 patients was 1116 days (37.2 months). The median PFS for patients without (n = 22) and with (n = 25) a decrease in their baseline hs-CRP was 326 days (11 months) vs. 3139 days (104 months) respectively (P <0.0001). The median overall survival (OS) for the 47 patients was 3482 days (9.5 years). The median OS for patients without and with a decrease in their baseline hs-CRP was 2885 days (7.9 years) vs. median not reached, respectively (P = 0.001). In SMM/IMM patients at risk for progression to active myeloma, reduction in the hs-CRP indicates successful targeting of the IL-1/IL-6 axis resulting in improved PFS and OS. (Clinical Trials.gov Identifier: NCT00635154) Am. J. Hematol. 91:571-574, 2016. © 2016 Wiley Periodicals, Inc. PMID:26945843

  4. E-Reserves Permissions and the Copyright Clearance Center: Process, Efficiency, and Cost

    ERIC Educational Resources Information Center

    Holobar, J. Christopher; Marshall, Andrew

    2011-01-01

    This study examines the process of requesting copyright permissions through the Copyright Clearance Center's (CCC) pay-per-use service for electronic course reserves at the Penn State University Libraries in 2008. The authors investigate the efficiency of this process as a function of the percentage of permission requests successfully mediated by…

  5. Latency reversal and viral clearance to cure HIV-1.

    PubMed

    Margolis, David M; Garcia, J Victor; Hazuda, Daria J; Haynes, Barton F

    2016-07-22

    Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society. PMID:27463679

  6. Necessary Clearance to Prevent Side Flashes

    NASA Astrophysics Data System (ADS)

    Shindo, Takatoshi; Asakawa, Akira; Honda, Hideki; Sakae, Maki; Tanaka, Shuusaku

    Side flashes often occur when lightning strikes a tree and cause injury or death of human beings staying nearby the tree. Necessary clearance to prevent the side flash has been said to be 2 m, but the physical meaning of the value is unclear. In this paper, we have proposed a model of side flashes based on the physics of discharges and necessary clearance has been calculated. Furthermore, we have carried out model experiments of the side flash using real trees of a heights of 3.5 m and a naturally growing tree of a height of more than 10 m. The results of the model experiments have verified the proposed theory and it is concluded that clearance of more than 3 m from a tree is necessary to prevent side flashes from the tree.

  7. Glycerol clearance in alcoholic liver disease.

    PubMed Central

    Johnston, D G; Alberti, K G; Wright, R; Blain, P G

    1982-01-01

    Glycerol clearance was studied by a primed dose-constant infusion technique in 14 patients with alcoholic liver disease and six normal control subjects. Fasting blood glycerol concentrations were raised in the alcoholic subjects (0.09 +/- 0.01 vs 0.06 +/- 0.01 mumol/l, p less than 0.05) and glycerol clearance was impaired (24.5 +/- 1.9 vs 37.5 +/- 3.2 ml/kg/min, p less than 0.005). Endogenous production rate of glycerol and distribution space at steady state were similar in alcoholic and control subjects. The metabolic clearance rate of glycerol correlated negatively with basal glycerol concentrations. Thus tissue uptake of glycerol is impaired in liver disease. As glycerol is metabolised primarily in the liver by conversion to glucose, these data suggest a defect of gluconeogenesis in alcoholic liver disease. PMID:7076002

  8. Pharmacologic agents for mucus clearance in bronchiectasis.

    PubMed

    Nair, Girish B; Ilowite, Jonathan S

    2012-06-01

    There are no approved pharmacologic agents to enhance mucus clearance in non-cystic fibrosis (CF) bronchiectasis. Evidence supports the use of hyperosmolar agents in CF, and studies with inhaled mannitol and hypertonic saline are ongoing in bronchiectasis. N-acetylcysteine may act more as an antioxidant than a mucolytic in other lung diseases. Dornase α is beneficial to patients with CF, but is not useful in patients with non-CF bronchiectasis. Mucokinetic agents such as β-agonists have the potential to improve mucociliary clearance in normals and many disease states, but have not been adequately studied in patients with bronchiectasis. PMID:22640851

  9. Prediction of hepatic microsomal intrinsic clearance and human clearance values for drugs.

    PubMed

    Nikolic, Katarina; Agababa, Danica

    2009-10-01

    Twenty-nine drugs of different structures were used in theoretical QSAR analysis of human hepatic microsomal intrinsic clearance (in vitro T(1/2) and in vitro CL'(int)) and whole body clearance (CL(blood)). The examined compounds demonstrated a wide range of scaled intrinsic clearance values. Constitutional, geometrical, physico-chemical and electronic descriptors were computed for the examined structures by use of the Marvin Sketch 5.1.3_2, the Chem3D Ultra 7.0.0 and the Dragon 5.4 program. Partial least squares regression (PLSR), has been applied for selection of the most relevant molecular descriptors and development of quantitative structure-activity relationship (QSAR) model for human hepatic microsomal intrinsic clearance (in vitro T(1/2)). Optimal QSAR models with nine and ten variables, R(2)>0.808 and cross-validation parameter q(pre)(2)>0.623, were selected and compared. Since the microsomal in vitro T(1/2) data can be used for calculation of in vitro CL'(int) and in vivo CL(blood), the developed QSAR model will enable one to analyze the kinetics of cytochrome P450-mediated reactions in term of intrinsic clearance and whole body clearance. A comparison is made between predictions produced from the QSAR analysis and experimental data, and there appears to be generally satisfactory correlations with the literature values for intrinsic clearance data. PMID:19713138

  10. Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves.

    PubMed

    McLean, Nikki A; Popescu, Bogdan F; Gordon, Tessa; Zochodne, Douglas W; Verge, Valerie M K

    2014-01-01

    Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies. PMID:25310564

  11. Dynamic clearance measure to evaluate locomotor and perceptuo-motor strategies used for obstacle circumvention in a virtual environment.

    PubMed

    Darekar, Anuja; Lamontagne, Anouk; Fung, Joyce

    2015-04-01

    Circumvention around an obstacle entails a dynamic interaction with the obstacle to maintain a safe clearance. We used a novel mathematical interpolation method based on the modified Shepard's method of Inverse Distance Weighting to compute dynamic clearance that reflected this interaction as well as minimal clearance. This proof-of-principle study included seven young healthy, four post-stroke and four healthy age-matched individuals. A virtual environment designed to assess obstacle circumvention was used to administer a locomotor (walking) and a perceptuo-motor (navigation with a joystick) task. In both tasks, participants were asked to navigate towards a target while avoiding collision with a moving obstacle that approached from either head-on, or 30° left or right. Among young individuals, dynamic clearance did not differ significantly between obstacle approach directions in both tasks. Post-stroke individuals maintained larger and smaller dynamic clearance during the locomotor and the perceptuo-motor task respectively as compared to age-matched controls. Dynamic clearance was larger than minimal distance from the obstacle irrespective of the group, task and obstacle approach direction. Also, in contrast to minimal distance, dynamic clearance can respond differently to different avoidance behaviors. Such a measure can be beneficial in contrasting obstacle avoidance behaviors in different populations with mobility problems. PMID:25682376

  12. Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo

    PubMed Central

    Zheng, Bo; von See, Marc P.; Yu, Elaine; Gunel, Beliz; Lu, Kuan; Vazin, Tandis; Schaffer, David V.; Goodwill, Patrick W.; Conolly, Steven M.

    2016-01-01

    Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R2 = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents. PMID:26909106

  13. Numerical analysis of blood flow in the clearance regions of a continuous flow artificial heart pump.

    PubMed

    Anderson, J; Wood, H G; Allaire, P E; Olsen, D B

    2000-06-01

    The CFVAD3 is the third prototype of a continuous flow ventricular assist device being developed for implantation in humans. The pump consists of a fully shrouded 4-blade impeller supported by magnetic bearings. On either side of this suspended rotating impeller is a small clearance region through which the blood flows. The spacing and geometry of these clearance regions are very important to the successful operation of this blood pump. Computational fluid dynamics (CFD) solutions for this flow were obtained using TascFlow, a software package available from AEA Technology, U.K. Flow in these clearance regions was studied parametrically by varying the size of the clearance, the blood flow rate into the pump, and the rotational speed of the pump. The numerical solutions yield the direction and magnitude of the flow and the dynamic pressure. Experimentally measured pump flow rates are compared to the numerical study. The results of the study provide guidance for improving pump efficiency. It is determined that current clearances can be significantly reduced to improve pump efficiency without negative impacts. PMID:10886072

  14. Tissue distribution, metabolism, and clearance of the convulsant trimethylolpropane phosphate in rats.

    PubMed

    Rossi, J; Jung, A E; Ritchie, G D; Lindsey, J W; Nordholm, A F

    1998-11-01

    The distribution, metabolism, and clearance of trimethylolpropane phosphate (TMPP), a potent, bicyclophosphate, gamma-aminobutyric acid-ergic convulsant, were studied in male Fischer-344 rats. Intraperitoneal administration of TMPP was compared with oral gavage with respect to rates of absorption, distribution, and clearance. Distribution of TMPP to major body tissues was evaluated for the first 24 hr after administration or, in the case of regional brain distribution, immediately after the first TMPP-induced clinical seizure. Samples purified from the urine, feces, and bile of rats exposed to TMPP, as well as from rat liver microsomes incubated with TMPP in vitro, were analyzed for possible phase I and phase II metabolism, using HPLC. The disposition and clearance of TMPP in the blood and major body tissues were measured. TMPP was found to be well distributed to highly vascularized tissue compartments, with little retention >24 hr after administration. TMPP was eliminated through the urine and feces as the parent compound, with no evidence of phase I or phase II metabolism. TMPP was rapidly cleared from the blood during the first 30 min after exposure, with slower clearance of >87% of the drug during the following 8-hr period and >99.5% clearance by 100 hr after injection. Repeated daily exposure to TMPP for up to 5 successive days resulted in no measurable accumulation in the brain or other major tissue compartments. Possible mechanisms for TMPP-induced, short- and long-term, neurobehavioral modulation are discussed. PMID:9806946

  15. Clearance of circulating radio-antibodies using streptavidin or second antibodies in a xenograft model.

    PubMed Central

    Marshall, D.; Pedley, R. B.; Boden, J. A.; Boden, R.; Begent, R. H.

    1994-01-01

    The improved tumour to non-tumour ratios needed for effective tumour targeting with antibodies requires that blood background radioactivity is reduced. We investigated the effect of streptavidin as a clearing agent for 125I-labelled biotinylated anti-CEA antibodies in a human colon carcinoma xenograft model. By comparing the biodistribution of the monoclonal antibody A5B7 with four, nine or 22 biotins per antibody molecule, we investigated how the degree of biotinylation of the primary radiolabelled antibody affects its clearance with streptavidin. Limiting the degree of biotinylation limited blood clearance, whereas nine or 22 biotins per antibody molecule resulted in a 13- to 14-fold reduction in blood radioactivity, the streptavidin-biotinylated antibody complexes clearing rapidly via the liver and spleen. Although a reduction in tumour activity was also seen, a 6.6-fold improvement in the tumour to blood ratio was achieved. A comparative study of streptavidin versus second antibody clearance was carried out using the polyclonal antibody PK4S biotinylated with 12 biotins per antibody molecule. This study indicated that second antibody was superior for clearance of the polyclonal antibody, resulting in a larger and faster reduction in blood radioactivity and improved tumour to blood ratios. In this case the primary antibody was polyclonal, and therefore non-uniformity of biotinylation may affect complexation with streptavidin. Therefore, the degree of biotinylation and type of antibody must be carefully considered before the use of streptavidin clearance. PMID:8123481

  16. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... be processed for a security clearance in accordance with 32 CFR part 353 and the provisions of this... shall be accomplished in accordance with 32 CFR part 159. The investigative requirement shall be the... security personnel who have no access to classified information. (11) To drivers, chauffeurs and...

  17. 32 CFR 154.16 - Security clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... be processed for a security clearance in accordance with 32 CFR part 353 and the provisions of this... shall be accomplished in accordance with 32 CFR part 159. The investigative requirement shall be the... security personnel who have no access to classified information. (11) To drivers, chauffeurs and...

  18. Mediators and mucociliary clearance in asthma.

    PubMed

    Pavia, D; Lopez-Vidriero, M T; Clarke, S W

    1987-01-01

    Lung mucociliary clearance is significantly reduced in asthmatic patients compared to healthy controls even during clinical remission. Further retardation in mucous clearance occurs during sleep per se and this may be a contributing factor to nocturnal asthma. Chemical mediators of anaphylaxis appear to have various and, sometimes opposing effects on the two essential components for mucociliary clearance, namely cilia and mucus. Some mediators such as leukotrienes C4 and D4 are potent secretagogues and histamine increases the water flux into the lumen of the airways from the mucosa. Slow-reacting substance of anaphylaxis (SRS-A) reduces mucus transport whereas histamine enhances it. Ciliostimulation has been reported following allergen challenge and this contrasts with the cilioinhibitory effect of asthmatics' sputa. It appears however, that the net effect of the various chemicals of anaphylaxis is one of impairment of mucus clearance. Some pharmacological agents, used for the relief of bronchospasm and control of asthma, also stimulate mucociliary transport, a desirable additional effect. PMID:3311245

  19. 28 CFR 524.74 - Activities clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Activities clearance. 524.74 Section 524.74 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INMATE ADMISSION, CLASSIFICATION, AND TRANSFER CLASSIFICATION OF INMATES Central Inmate Monitoring (CIM) System § 524.74...

  20. 30 CFR 57.11008 - Restricted clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 57.11008 Section 57.11008 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Travelways and Escapeways Travelways-Surface and Underground §...

  1. 30 CFR 57.11010 - Stairstep clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Stairstep clearance. 57.11010 Section 57.11010 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Travelways and Escapeways Travelways-Surface and Underground...

  2. 15 CFR 752.15 - Export clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... accordance with requirements of the Foreign Trade Statistics Regulations (15 CFR part 30) and § 758.1 of the... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Export clearance. 752.15 Section 752... OF INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE EXPORT ADMINISTRATION REGULATIONS...

  3. Acute psychological stress reduces plasma triglyceride clearance.

    PubMed

    Stoney, Catherine M; West, Sheila G; Hughes, Joel W; Lentino, Lisa M; Finney, Montenique L; Falko, James; Bausserman, Linda

    2002-01-01

    Acute stress elevates blood lipids, with the largest increases among men and postmenopausal women. The mechanisms for the effect are unknown, but may be due to altered lipid metabolism. This study investigated if acute stress induces transient reductions in triglyceride clearance in middle-aged men and women, and determined if gender and menopause affect triglyceride metabolism. Of the 35 women, half were premenopausal, and half were naturally postmenopausal; men (n = 35) were age matched. Clearance of an intravenously administered fat emulsion was assessed twice: once during a nonstress session, and again during a stress-testing session. During the stress session, a battery of behavioral stressors (serial subtraction, speech, mirror tracing, and Stroop) were performed for 40 min. The clearance rate of exogenous fat was significantly diminished during the stress, relative to the nonstress session. Women had more efficient clearance, relative to men, but there were no effects of menopausal status. The diminished ability to clear an intravenous fat emulsion during stress suggests one mechanism for stress-induced elevations in lipids. PMID:12206298

  4. 49 CFR 192.325 - Underground clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Underground clearance. 192.325 Section 192.325 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY TRANSPORTATION OF NATURAL AND OTHER GAS BY PIPELINE: MINIMUM...

  5. Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease

    PubMed Central

    2013-01-01

    Recent evidence in humans indicate that defective phagocytic clearance of dying cells is linked to progression of advanced atherosclerotic lesions, the precursor to atherothrombosis, ischemic heart disease, and leading cause of death in the industrialized world. During atherogenesis, apoptotic cell turnover in the vascular wall is counterbalanced by neighboring phagocytes with high clearance efficiency, thereby limiting cellularity and maintaining lesion integrity. However, as lesions mature, phagocytic removal of apoptotic cells (efferocytosis) becomes defective, leading to secondary necrosis, expansion of plaque necrotic cores, and susceptibility to rupture. Recent genetic causation studies in experimental rodents have implicated key molecular regulators of efferocytosis in atherosclerotic progression. These include MER tyrosine kinase (MERTK), milk fat globule-EGF factor 8 (MFGE8), and complement C1q. At the cellular level, atheromata are infiltrated by a heterogenous population of professional phagocytes, comprised of monocytes, differentiated macrophages, and CD11c+ dendritic-like cells. Each cell type is characterized by disparate clearance efficiencies and varying activities of key phagocytic signaling molecules. It is in this context that we outline a working model whereby plaque necrosis and destabilization is jointly promoted by (1) direct inhibition of core phagocytic signaling pathways and (2) expansion of phagocyte subsets with poor clearance capacity. Towards identifying targets for promoting efficient apoptotic cell clearance and resolving inflammation in atherosclerosis and during ischemic heart disease and post myocardial infarction, this review will discuss potential in vivo suppressors of efferocytosis at each stage of clearance and how these putative interventional targets may differentially affect uptake at the level of vascular phagocyte subsets. PMID:20552278

  6. Relative importance of magnetic moments in UXO clearance applications

    USGS Publications Warehouse

    Sanchez, V.; Li, Y.; Nabighian, M.; Wright, D.

    2006-01-01

    Surface magnetic anomaly observed in UXO clearance is mainly dipolar and, as a result, the dipole is the only moment used regularly in UXO applications. The dipole moment contains intensity of magnetization information but lacks shape information. Unlike dipole, higher-order moments, such as quadrupole and octupole, encode asymmetry properties of magnetization distribution within buried targets. In order to improve our understanding of magnetization distribution within UXO and non-UXO objects and its potential utility in UXO clearance, we present results of a 3D numerical modeling study for highly susceptible metallic objects. The basis for modeling is the solution of a nonlinear integral equation, describing magnetization within isolated objects, allowing us to compute magnetic moments of the object, analyze their relationships, and provide a depiction of the surface anomaly produced by the different moments within the object. Our modeling results show significant high-order moments for more asymmetric objects situated at typical UXO burial depths, and suggest that the increased relative contribution to magnetic gradient data from these higher-order moments may provide a practical tool for improved UXO discrimination. ?? 2005 Society of Exploration Geophysicists.

  7. 75 FR 70341 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-17

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security..._Submission@omb.eop.gov . (SSA), Social Security Administration, DCBFM, Attn: Reports Clearance Officer,...

  8. 19 CFR 122.26 - Entry and clearance.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... AIR COMMERCE REGULATIONS Private Aircraft § 122.26 Entry and clearance. Private aircraft, as defined... information as set forth in § 122.22(c), and grants electronic clearance via electronic mail or telephone....

  9. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REGULATIONS NAVIGATION OF FOREIGN CIVIL AIRCRAFT WITHIN THE UNITED STATES Rules Generally Applicable § 375.24 Entry and clearance. All U.S. entry and clearance requirements for aircraft, passengers, crews,...

  10. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REGULATIONS NAVIGATION OF FOREIGN CIVIL AIRCRAFT WITHIN THE UNITED STATES Rules Generally Applicable § 375.24 Entry and clearance. All U.S. entry and clearance requirements for aircraft, passengers, crews,...

  11. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... REGULATIONS NAVIGATION OF FOREIGN CIVIL AIRCRAFT WITHIN THE UNITED STATES Rules Generally Applicable § 375.24 Entry and clearance. All U.S. entry and clearance requirements for aircraft, passengers, crews,...

  12. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... REGULATIONS NAVIGATION OF FOREIGN CIVIL AIRCRAFT WITHIN THE UNITED STATES Rules Generally Applicable § 375.24 Entry and clearance. All U.S. entry and clearance requirements for aircraft, passengers, crews,...

  13. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance. (a... pertinent laws, and the nature of international security and information exchange agreements. The...

  14. 77 FR 44641 - Critical Infrastructure Private Sector Clearance Program Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-30

    ... SECURITY Critical Infrastructure Private Sector Clearance Program Request AGENCY: National Protection and... Programs Directorate (NPPD), Office of Infrastructure Protection (IP) will submit the following Information... Infrastructure Private Sector Clearance Program (PSCP). DHS previously published this ICR in the Federal...

  15. 77 FR 21989 - Critical Infrastructure Private Sector Clearance Program Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... SECURITY Critical Infrastructure Private Sector Clearance Program Request AGENCY: National Protection and... Programs Directorate (NPPD), Office of Infrastructure Protection (IP) will submit the following Information... information provided. SUPPLEMENTARY INFORMATION: The Critical Infrastructure Private Sector Clearance...

  16. WWW-based data entry for document clearance requests

    SciTech Connect

    Stasiak, D.M.

    1997-10-08

    All documents created at Argonne must be cleared before being published. The clearance process is coordinated by the Publications and Record Services. The Electronic Document Review and Clearance System (EDRC) consists of a Web-based system for submission of clearance requests, an electronic staging area for document awaiting review, and Web-based review and clearance of documents. This report covers the document clearing process, the EDRC system, expected benefits/costs, and a demonstration.

  17. 30 CFR 56.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance on adjacent tracks. 56.9103 Section..., Hauling, and Dumping Traffic Safety § 56.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  18. 30 CFR 57.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Clearance on adjacent tracks. 57.9103 Section..., Hauling, and Dumping Traffic Safety § 57.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  19. 30 CFR 56.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Clearance on adjacent tracks. 56.9103 Section..., Hauling, and Dumping Traffic Safety § 56.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  20. 30 CFR 57.9103 - Clearance on adjacent tracks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance on adjacent tracks. 57.9103 Section..., Hauling, and Dumping Traffic Safety § 57.9103 Clearance on adjacent tracks. Railcars shall not be left on side tracks unless clearance is provided for traffic on adjacent tracks....

  1. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING..., App. B Appendix B to Part 1327—OMB Clearance The OMB clearance number of this regulation is OMB...

  2. 61 FR 11709 - Real Estate Title Clearance and Loan Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    1996-03-22

    ... 0575-AB52 Real Estate Title Clearance and Loan Closing AGENCIES: Rural Housing Service, Rural Business... ``agency,'' amend the Real Estate Title Clearance and Loan Closing regulation. This action makes loan.... The proposed rule discussed the need to make real estate title clearance and loan closing...

  3. 59 FR- Real Estate Title Clearance and Loan Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    1994-05-11

    .... SUMMARY: The Farmers Home Administration (FmHA) proposes to amend its Real Estate Title Clearance and Loan... changes affect FmHA processing, real estate title clearance, and loan closing. Paperwork Reduction Act The... EO. Discussion FmHA recognizes the need to make Real Estate Title Clearance and Loan...

  4. 14 CFR 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Customs clearance and visas. 1260.63 Section 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance and Visas...

  5. 14 CFR 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Customs clearance and visas. 1260.63 Section 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance and Visas...

  6. 14 CFR 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Customs clearance and visas. 1260.63 Section 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance and Visas...

  7. 14 CFR § 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Customs clearance and visas. § 1260.63 Section § 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance...

  8. 14 CFR 1260.63 - Customs clearance and visas.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Customs clearance and visas. 1260.63 Section 1260.63 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Special Conditions § 1260.63 Customs clearance and visas. Customs Clearance and Visas...

  9. Wear analysis of revolute joints with clearance in multibody systems

    NASA Astrophysics Data System (ADS)

    Bai, ZhengFeng; Zhao, Yang; Wang, XingGui

    2013-08-01

    In this work, the prediction of wear for revolute joint with clearance in multibody systems is investigated using a computational methodology. The contact model in clearance joint is established using a new hybrid nonlinear contact force model and the friction effect is considered by using a modified Coulomb friction model. The dynamics model of multibody system with clearance is established using dynamic segmentation modeling method and the computational process for wear analysis of clearance joint in multibody systems is presented. The main computational process for wear analysis of clearance joint includes two steps, which are dynamics analysis and wear analysis. The dynamics simulation of multibody system with revolute clearance joint is carried out and the contact forces are drawn and used to calculate the wear amount of revolute clearance joint based on the Archard's wear model. Finally, a four-bar multibody mechanical system with revolute clearance joint is used as numerical example application to perform the simulation and show the dynamics responses and wear characteristics of multibody systems with revolute clearance joint. The main results of this work indicate that the contact between the joint elements is wider and more frequent in some specific regions and the wear phenomenon is not regular around the joint surface, which causes the clearance size increase non-regularly after clearance joint wear. This work presents an effective method to predict wear of revolute joint with clearance in multibody systems.

  10. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Processing facility clearance. 95.17 Section 95.17 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance. (a) Following the receipt of an acceptable...

  11. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  12. 48 CFR 945.670-1 - Plant clearance function.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... contracting officer shall assume all responsibilities of the plant clearance officer identified in 48 CFR 45... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Plant clearance function... MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 945.670-1 Plant clearance function....

  13. 48 CFR 945.670-1 - Plant clearance function.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... contracting officer shall assume all responsibilities of the plant clearance officer identified in 48 CFR 45... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Plant clearance function... MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 945.670-1 Plant clearance function....

  14. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  15. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  16. 48 CFR 245.602-70 - Plant clearance procedures.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Plant clearance procedures... Disposal 245.602-70 Plant clearance procedures. Follow the procedures at PGI 245.602-70 for establishing and processing a plant clearance case....

  17. 33 CFR 157.455 - Minimum under-keel clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Minimum under-keel clearance. 157... § 157.455 Minimum under-keel clearance. (a) The owner or operator of a tankship, that is not fitted with... written under-keel clearance guidance that includes— (1) Factors to consider when calculating the...

  18. 33 CFR 157.455 - Minimum under-keel clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Minimum under-keel clearance. 157... § 157.455 Minimum under-keel clearance. (a) The owner or operator of a tankship, that is not fitted with... written under-keel clearance guidance that includes— (1) Factors to consider when calculating the...

  19. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 5 2011-04-01 2011-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  20. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  1. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  2. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  3. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  4. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  5. 46 CFR 56.75-10 - Joint clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Joint clearance. 56.75-10 Section 56.75-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Brazing § 56.75-10 Joint clearance. (a) The clearance between surfaces to be joined shall be...

  6. 30 CFR 56.9330 - Clearance for surface equipment.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Clearance for surface equipment. 56.9330... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Loading... Dumping Sites § 56.9330 Clearance for surface equipment. Continuous clearance of at least 30 inches...

  7. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... clearances (PCLs); and (4) Appointing a U.S. citizen employee as the facility security officer. (b) An... NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance....

  8. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  9. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 5 2013-04-01 2013-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  10. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 5 2012-04-01 2012-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  11. 10 CFR 95.23 - Termination of facility clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.23 Termination of facility clearance. (a... determination that continued facility clearance is not in the interest of national security. (b) When...

  12. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rotor blade clearance. 27.661 Section 27... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  13. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Rotor blade clearance. 29.661 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  14. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Rotor blade clearance. 27.661 Section 27... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  15. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Rotor blade clearance. 29.661 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  16. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Rotor blade clearance. 29.661 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  17. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Rotor blade clearance. 29.661 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  18. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Rotor blade clearance. 27.661 Section 27... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  19. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Rotor blade clearance. 27.661 Section 27... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  20. 14 CFR 27.661 - Rotor blade clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Rotor blade clearance. 27.661 Section 27... AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Design and Construction Rotors § 27.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  1. 14 CFR 29.661 - Rotor blade clearance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rotor blade clearance. 29.661 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Design and Construction Rotors § 29.661 Rotor blade clearance. There must be enough clearance between the rotor blades and other parts of the structure...

  2. Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Lattime, Scott B.; Taylor, Shawn; DeCastro, Jonathan A.; Oswald, Jay; Melcher, Kevin J.

    2005-01-01

    Reducing blade tip clearances through active tip clearance control in the high pressure turbine can lead to significant reductions in emissions and specific fuel consumption as well as dramatic improvements in operating efficiency and increased service life. Current engines employ scheduled cooling of the outer case flanges to reduce high pressure turbine tip clearances during cruise conditions. These systems have relatively slow response and do not use clearance measurement, thereby forcing cold build clearances to set the minimum clearances at extreme operating conditions (e.g., takeoff, reburst) and not allowing cruise clearances to be minimized due to the possibility of throttle transients (e.g., step change in altitude). In an effort to improve upon current thermal methods, a first generation mechanically-actuated active clearance control (ACC) system has been designed and fabricated. The system utilizes independent actuators, a segmented shroud structure, and clearance measurement feedback to provide fast and precise active clearance control throughout engine operation. Ambient temperature performance tests of this first generation ACC system assessed individual seal component leakage rates and both static and dynamic overall system leakage rates. The ability of the nine electric stepper motors to control the position of the seal carriers in both open- and closed-loop control modes for single and multiple cycles was investigated. The ability of the system to follow simulated engine clearance transients in closed-loop mode showed the system was able to track clearances to within a tight tolerance ( 0.001 in. error).

  3. Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Lattime, Scott B.; DeCastro, Jonathan A.; Oswald, Jay; Melcher, Kevin J.

    2005-01-01

    Reducing blade tip clearances through active tip clearance control in the high pressure turbine can lead to significant reductions in emissions and specific fuel consumption as well as dramatic improvements in operating efficiency and increased service life. Current engines employ scheduled cooling of the outer case flanges to reduce high pressure turbine tip clearances during cruise conditions. These systems have relatively slow response and do not use clearance measurement, thereby forcing cold build clearances to set the minimum clearances at extreme operating conditions (e.g., takeoff, reburst) and not allowing cruise clearances to be minimized due to the possibility of throttle transients (e.g., step change in altitude). In an effort to improve upon current thermal methods, a first generation mechanically-actuated active clearance control (ACC) system has been designed and fabricated. The system utilizes independent actuators, a segmented shroud structure, and clearance measurement feedback to provide fast and precise active clearance control throughout engine operation. Ambient temperature performance tests of this first generation ACC system assessed individual seal component leakage rates and both static and dynamic overall system leakage rates. The ability of the nine electric stepper motors to control the position of the seal carriers in both open- and closed-loop control modes for single and multiple cycles was investigated. The ability of the system to follow simulated engine clearance transients in closed-loop mode showed the system was able to track clearances to within a tight tolerance (0.001 in. error).

  4. Axial compressor blade design for desensitization of aerodynamic performance and stability to tip clearance

    NASA Astrophysics Data System (ADS)

    Erler, Engin

    of the local blade passage. These flow features are isolated and validated based on the reference rotor design through changes in the inlet total pressure condition to alter incoming flow momentum and blade number count to change double leakage rate. In terms of flow mechanism, double leakage is shown to be detrimental to performance and stability, and its proportional increase with tip clearance size explains the sensitivity increase in the presence of double leakage and, conversely, the desensitization effect of reducing or eliminating double leakage. The increase in incoming meridional momentum in the tip region reduces sensitivity to tip clearance through its reduction of double leakage as well as through improved mixing with tip clearance flow, as demonstrated by an analytical model without double leakage flow. The above results imply that any blade design strategy that exploits the two desensitizing flow features would reduce the performance and stability sensitivity to tip clearance size. The increase of the incoming meridional momentum can be achieved through forward chordwise sweep of the blade. The reduction of double leakage without changing blade pitch can be obtained by decreasing the blade stagger angle in the tip region. Examples of blade designs associated with these strategies are shown through CFX simulations to be successful in reducing sensitivity to tip clearance size.

  5. Success and Challenges of a Community Healthy Lifestyles Intervention in Merseyside (UK) to Target Families at Risk from Coronary Heart Disease

    ERIC Educational Resources Information Center

    Peerbhoy, D.; Majumdar, A. J.; Wightman, N. A.; Brand, V. L.

    2008-01-01

    Objective: To document the lifestyle health impacts (activity, diet and physiological), along with the operational success and challenges, of a programme for families presenting one or more coronary heart disease (CHD) risk factor. Design: Data are based on a wider evaluation of a government-funded community initiative conducted in a deprived area…

  6. The Effect of Contingent Reinforcement on Target Variables in Outpatient Psychotherapy for Depression: A Successful and Unsuccessful Case Using Functional Analytic Psychotherapy

    ERIC Educational Resources Information Center

    Kanter, Jonathan W.; Landes, Sara J.; Busch, Andrew M.; Rusch, Laura C.; Brown, Keri R.; Baruch, David E.; Holman, Gareth I.

    2006-01-01

    The current study investigated a behavior-analytic treatment, functional analytic psychotherapy (FAP), for outpatient depression utilizing two single-subject A/A+B designs. The baseline condition was cognitive behavioral therapy. Results demonstrated treatment success in 1 client after the addition of FAP and treatment failure in the 2nd. This…

  7. HPV Clearance and the Neglected Role of Stochasticity

    PubMed Central

    Ryser, Marc D.; Myers, Evan R.; Durrett, Rick

    2015-01-01

    Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance—in form of the stochastic dynamics of basal stem cells—plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance—the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible. PMID:25769112

  8. Gas turbine engine active clearance control

    NASA Technical Reports Server (NTRS)

    Deveau, Paul J. (Inventor); Greenberg, Paul B. (Inventor); Paolillo, Roger E. (Inventor)

    1985-01-01

    Method for controlling the clearance between rotating and stationary components of a gas turbine engine are disclosed. Techniques for achieving close correspondence between the radial position of rotor blade tips and the circumscribing outer air seals are disclosed. In one embodiment turbine case temperature modifying air is provided in flow rate, pressure and temperature varied as a function of engine operating condition. The modifying air is scheduled from a modulating and mixing valve supplied with dual source compressor air. One source supplies relatively low pressure, low temperature air and the other source supplies relatively high pressure, high temperature air. After the air has been used for the active clearance control (cooling the high pressure turbine case) it is then used for cooling the structure that supports the outer air seal and other high pressure turbine component parts.

  9. Autophagy promotes DNA-protein crosslink clearance.

    PubMed

    Mu, Haibo; Liu, Qianjin; Niu, Hong; Wang, Dongdong; Tang, Jiangjiang; Duan, Jinyou

    2016-02-01

    Toxic DNA-protein crosslinks (DPCs) can result from exposure to radiation or chemotherapeutic agents. DPCs can also accumulate during aging or stress. However, the cellular mechanisms underlying clearance of DPCs remain largely unknown. Here, we have identified an important role of autophagy in the processing of DPCs induced by three representative agents: formaldehyde, a chemical used widely in industry; UV light; and camptothecin, a cytotoxic anticancer drug. Autophagy inhibitors, 3-methyladenine (3-MA) or chloroquine (CQ), promoted the accumulation of DPCs in damaged cells and injured organs. siRNA-mediated silencing of Atg5 or Atg7, two essential components for the formation of the autophagosome, gave similar results. In contrast, the autophagy inducer rapamycin (RAP) attenuated DPCs in vitro and in vivo. Our findings reveal the importance of autophagy in controlling the level of DPCs, and may open up a new avenue for understanding the formation and clearance of this detrimental DNA adduct. PMID:26921017

  10. High-Clearance Six-Wheel Suspension

    NASA Technical Reports Server (NTRS)

    Bickler, Donald B.

    1992-01-01

    Multilevered suspension system gives body of vehicle high clearance and allows wheels to be steered independently. Suspension linkages above wheels enable body to skim over obstacles as high as wheel. Levers and independently steered wheels enable vehicle to climb steps 1 1/2 wheel diameters high and cross gaps 1 3/4 wide. Adaptable to off-the-road recreational vehicles, military scout vehicles, and robotic emergency vehicles.

  11. Instrument for Measuring Engine Clearance Volumes

    NASA Technical Reports Server (NTRS)

    Sparrow, S W

    1920-01-01

    With the advent of the V type engine, a new method to measure the clearance volume in cylinders was needed. It was suggested that this measurement could be made by a process which consisted essentially of simultaneously changing both a known and unknown volume of gas by a known amount and then calculating the magnitude of the unknown from the resulting difference in pressure between the two. An instrument based on this design is described.

  12. Deposition and clearance of inhaled particles.

    PubMed Central

    Stuart, B O

    1976-01-01

    Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as determined principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of convenient approximations of the respiratory tract to predict tractional deposition according to fundamental physical processes of impaction, sedimentation, and diffusion. These theoretical models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with experimental studies of inhaled dusts in humans or experimental animals that have been performed in many laboratories over several decades. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior of very fine (less than 0.01 mum) particles requires further refinement.Properties of particle shape, charge, and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns and further experimental work is urgently needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of such techniques with selected inhaled particle size holds promise in possible diagnostic aid in diagnosis of normal versus disease conditions. Mechanisms of conducting airway and alveolar clearance processes involving mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic clearance are discussed. The roles of the pulmonary macrophage in airway and alveolar clearance are described, and the applicability of recent solubility models for translocation or deposited materials to liver, skeleton, or other systemic organs is discussed. PMID:797567

  13. The effect of solubility on inhaled uranium compound clearance: a review.

    PubMed

    Eidson, A F

    1994-07-01

    Research on inhaled industrial uranium compounds has shown that solubility influences the target organ, the toxic response, and the mode of uranium excretion. Consideration of physical chemical properties indicates that the dissolution of industrial uranium oxides is expected to be strongly dependent on process history, and that dissolved uranium exists in vivo in the hexavalent state regardless of the oxidation state of the inhaled compound. The overall clearance rate of uranium compounds from the lung reflects both mechanical and dissolution processes. Mechanical clearance rates are highly variable among individual workers studied, but dissolution rates of inhaled compounds are similar among the mammalian species studied. Results from experiments in vivo and accidental worker exposures indicate that the uptake of dissolved uranium from the lung is more rapid than the dissolution rate of most industrial uranium compounds. These results indicate that the absorption rate of inhaled uranium can be approximated by the dissolution rate of most industrial compounds. Dissolution rates of UF6 and UO2(NO3)2 are more rapid than the mechanical clearance rates and dominate the overall lung clearance rate. UF4, UO3, and ammonium diuranate have intermediate dissolution rates that are similar to mechanical clearance rates and exhibit high variability among uranium specimens. U3O8 and UO2 have slow dissolution rates such that pulmonary clearance rates are dominated by mechanical processes. Industrial uranium ores, oxides, and fluorides are often variable mixtures of relatively soluble and insoluble fractions. Dissolution rates measured in vitro can be used with biokinetics models to reduce the uncertainties in dosimetry associated with inhalation exposures to mixtures. PMID:8200796

  14. Impact of glycation on antibody clearance.

    PubMed

    Yang, Jane; Primack, Ronya; Frohn, Mike; Wang, Wei; Luan, Peng; Retter, Marc W; Flynn, Gregory C

    2015-01-01

    Glycation of therapeutic proteins occurs during mammalian cell culture expression and upon administration to patients. Since the chemical attachment of mannose or other sugars via a chemical linker has been shown to increase a protein's clearance rate in mice through the mannose receptor, we explored the effect of mannose glycation on the clearance of an IgG in mice. An IgG decorated with high levels of mannose (~18 mol/mol protein) through glycation did not clear faster in mice than the underivatized protein, whereas the same IgG decorated with mannose attached in a way to maintain the normal glycosidic bond (2-imino-2-methoxyethyl-1-thiomannoside, or IMT-mannose) at similar derivatization levels cleared significantly faster. Surface plasmon resonance studies revealed that the IgG derivatized with IMT-mannose bound tightly to the mannose receptor (KD = 20 nM) but the IgG glycated with mannose did not bind. These results indicate that glycation, even at unnaturally elevated levels, does not appear to be a clearance concern for therapeutic proteins. PMID:25413724

  15. Similarity analysis of compressor tip clearance flow structure

    NASA Technical Reports Server (NTRS)

    Chen, G. T.; Greitzer, E. M.; Tan, C. S.; Marble, F. E.

    1991-01-01

    A new approach is presented for analyzing compressor tip clearance flow. The basic idea is that the clearance velocity field can be (approximately) decomposed into independent throughflow and crossflow, since chordwise pressure gradients are much smaller than normal pressure gradients in the clearance region. As in the slender body approximation in external aerodynamics, this description implies that the three-dimensional steady clearance flow can be viewed as a two-dimensional, unsteady flow. Using this approach, a similarity scaling for the crossflow in the clearance region is developed and a generalized description of the clearance vortex is derived. Calculations based on the similarity scaling agree well with a wide range of experimental data in regard to flow features such as crossflow velocity field, static pressure field, and tip clearance vortex trajectory.

  16. Analysis and experimental study of the spherical joint clearance

    NASA Astrophysics Data System (ADS)

    Zhao, Peng; Hu, Penghao; Bao, Xinxin; Li, Shuaipeng

    2013-10-01

    The spherical joint clearance is a key error factor, which influenced and restricted the application of parallel mechanism in high precision field. This paper discusses the regularity of the spherical joint clearance in the parallel mechanism and its influence on the accuracy of the parallel mechanism in both theoretical and experimental aspects. A spherical joint clearance measuring instrument is introduced and used to measure the joint clearance. And the relationship between the clearance and its work pose is revealed. Based on the theoretical and experimental analysis, it is concluded that the clearance of the spherical joint is near-linear proportional to the applied load as well as the clearances in different poses obey the Rayleigh distribution approximately under the same load.

  17. Targeted therapy using nanotechnology: focus on cancer

    PubMed Central

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

  18. Deposition, retention, and clearance of inhaled particles.

    PubMed Central

    Lippmann, M; Yeates, D B; Albert, R E

    1980-01-01

    The relation between the concentrations and characteristics of air contaminants in the work place and the resultant toxic doses and potential hazards after their inhalation depends greatly on their patterns of deposition and the rates and pathways for their clearance from the deposition sites. The distribution of the deposition sites of inhaled particles is strongly dependent on their aerodynamic diameters. For normal man, inhaled non-hygroscopic particles greater than or equal to 2 micrometers that deposit in the conducting airways by impaction are concentrated on to a small fraction of the surface. Cigarette smoking and bronchitis produce a proximal shift in the deposition pattern. The major factor affecting the deposition of smaller particles is their transfer from tidal to reserve air. For particles soluble in respiratory tract fluid, systemic uptake may be relatively complete for all deposition patterns, and there may be local toxic or irritant effects or both. On the other hand, slowly soluble particles depositing in the conducting airways are carried on the surface to the glottis and are swallowed within one day. Mucociliary transport rates are highly variable, both along the ciliated airways of a given individual and between individuals. The changes in clearance rates produced by drugs, cigarette smoke, and other environmental pollutants can greatly increase or decrease these rates. Particles deposited in non-ciliated airways have large surface-to-volume ratios, and clearance by dissolution can occur for materials generally considered insoluble. They may also be cleared as free particles either by passive transport along surface liquids or, after phagocytosis, by transport within alveolar macrophages. If the particles penetrate the epithelium, either bare or within macrophages, they may be sequestered within cells or enter the lymphatic circulation and be carried to pleural, hilar, and more distant lymph nodes. Non-toxic insoluble particles are cleared from

  19. Early stages of simian immunodeficiency virus infection in lymph nodes. Evidence for high viral load and successive populations of target cells.

    PubMed Central

    Chakrabarti, L.; Isola, P.; Cumont, M. C.; Claessens-Maire, M. A.; Hurtrel, M.; Montagnier, L.; Hurtrel, B.

    1994-01-01

    Lymph nodes obtained from 14 macaques sacrificed at early time points following experimental inoculation with simian immunodeficiency virus were analyzed by in situ hybridization for virus load and virus cellular tropism. The lymph nodes presented a remarkably high viral load during the early phase of infection, as viral RNA was detected in as many as 2% of lymph node cells 1 week after inoculation. At this stage, macrophages and T4 lymphocytes were identified by combined immunohistochemistry and in situ hybridization as the target cells of the virus. Simian immunodeficiency virus-positive macrophages concentrated in the subcapsular sinuses, suggesting an entry of infected cells via the afferent lymphatics. A shift in the pattern of viral infection was observed at 2 weeks after inoculation, with a concentration of viral RNA in the germinal centers of the developing lymphoid follicles. Follicular dendritic cells were found to be the major target of the virus at this stage. Follicular dendritic cells were associated with high levels of viral RNA but little or no detectable viral DNA, suggesting that the virus was present mostly in the form of viral particles trapped at the cell surface. Follicular dendritic cell-associated virus persisted at high levels for 2 months before subsiding, indicating that follicular dendritic cells constituted a major reservoir of the virus during the early stages of simian immunodeficiency virus infection. Images Figure 2 Figure 4 Figure 5 Figure 6 PMID:8203463

  20. Testing of a Microwave Blade Tip Clearance Sensor at the NASA Glenn Research Center

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Roeder, James W.; Hughes, Christopher E.; Bencic, Timothy J.

    2009-01-01

    The development of new active tip clearance control and structural health monitoring schemes in turbine engines and other types of rotating machinery requires sensors that are highly accurate and can operate in a high temperature environment. The use of a microwave sensor to acquire blade tip clearance and tip timing measurements is being explored at the NASA Glenn Research Center. The microwave blade tip clearance sensor works on principles that are very similar to a short range radar system. The sensor sends a continuous microwave signal towards a target and measures the reflected signal. The phase difference of the reflected signal is directly proportional to the distance between the sensor and the target being measured. This type of sensor is beneficial in that it has the ability to operate at extremely high temperatures and is unaffected by contaminants that may be present in turbine engines. The use of microwave sensors for this application is a new concept. Techniques on calibrating the sensors along with installation effects are not well quantified as they are for other sensor technologies. Developing calibration techniques and evaluating installation effects are essential in using these sensors to make tip clearance and tip timing measurements. As a means of better understanding these issues, the microwave sensors were used on a bench top calibration rig, a large axial vane fan, and a turbofan. Background on the microwave tip clearance sensor, an overview of their calibration, and the results from their use on the axial vane fan and the turbofan will be presented in this paper.

  1. Testing of a Microwave Blade Tip Clearance Sensor at the NASA Glenn Research Center

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Roeder, James W.; Hughes, Christopher E.; Bencic, Timothy J.

    2009-01-01

    The development of new active tip clearance control and structural health monitoring schemes in turbine engines and other types of rotating machinery requires sensors that are highly accurate and can operate in a high-temperature environment. The use of a microwave sensor to acquire blade tip clearance and tip timing measurements is being explored at the NASA Glenn Research Center. The microwave blade tip clearance sensor works on principles that are very similar to a short-range radar system. The sensor sends a continuous microwave signal towards a target and measures the reflected signal. The phase difference of the reflected signal is directly proportional to the distance between the sensor and the target being measured. This type of sensor is beneficial in that it has the ability to operate at extremely high temperatures and is unaffected by contaminants that may be present in turbine engines. The use of microwave sensors for this application is a new concept. Techniques on calibrating the sensors along with installation effects are not well quantified as they are for other sensor technologies. Developing calibration techniques and evaluating installation effects are essential in using these sensors to make tip clearance and tip timing measurements. As a means of better understanding these issues, the microwave sensors were used on a benchtop calibration rig, a large axial vane fan, and a turbofan. Background on the microwave tip clearance sensor, an overview of their calibration, and the results from their use on the axial vane fan and the turbofan will be presented in this paper.

  2. Intrinsic Clearance of Xenobiotic Chemicals by Liver Microsomes: Assessment of Trophic Magnification Potentials.

    PubMed

    Guomao, Zheng; Yi, Wan; Jianying, Hu

    2016-06-21

    The use of trophic magnification factors (TMFs) to characterize the bioaccumulation potentials of chemicals was encouraged; however, the method for the assessment of trophic magnification potentials is still lacking. We optimized the in vitro assays used for the measurement of intrinsic clearance in liver microsomes by incorporating benzo[a]pyrene (B(a)P) as a benchmark compound. The intrinsic clearance of 40 compounds was then measured in microsomes from fish (weevers) and birds (quail); the characteristics of the trophic transfer of these 40 compounds were previously investigated in an aquatic food web in Bohai in northern China. Chemicals that are biotransformed at a rate similar to or higher than that of B[a]P in the microsomes of both weevers and quail (in vitro intrinsic clearance values, CL; CL/CLB[a]P: 0.1 to 2.4) generally exhibited no significant trophic magnification or dilution in the food web (TMF ≈ 1 or < 1), whereas chemicals that are biotransformed at extremely slow rates compared with B[a]P (CL/CLB[a]P: 0 to 0.2) showed significant trophic magnification in the food web (TMF > 1). The in vitro intrinsic clearance values of the target chemicals were found to be consistent with their respective trophic transfer behavior in the aquatic food web. Significant negative correlations were also found between the TMFs and the intrinsic clearance values of all target chemicals obtained in microsomes from both weevers and quail. Multiple linear regression analysis showed that biotransformation rates (CL/CLB[a]P) are a more important factor compared with the lipophilicity of the chemicals (log Kow) in the assessment of the trophic magnification of chemicals in the aquatic food web. PMID:27152959

  3. Evaluation Method of Gas Leakage Flow Through Small Clearances in CO2 Scroll Compressors

    NASA Astrophysics Data System (ADS)

    Ishii, Noriaki; Oku, Tatsuya; Anami, Keiko; Sawai, Kiyoshi; Sano, Kiyoshi; Morimoto, Takashi

    This study presents an evaluation method of leakage flow through small axial and radial clearances between the orbiting and fixed scrolls of scroll compressors, where empirical friction factors were addressed. Leakage flow experiments were conducted for two refrigerants, CO2 and R22, flowing through the small axial and radial clearance models with a thin rectangular cross-sectional opening. The pressure drop in a pressurized closed vessel, due to leakage, was measured at a variety of initial pressure up to 3 MPa for CO2 and 0.6 MPa for R22. Darcy-Weisbach equation for the incompressible viscous fluid flow through the circular pipe was successfully applied to calculate the pressure drop due to leakage through the thin rectangular cross-section, where the empirical friction factors were determined and plotted on a Moody diagram. It was concluded that the working fluids are compressible and the leakage flow through the small clearances can be treated as the incompressible viscous fluid, where both the axial and radial clearance leakage flows can be represented by the same friction factor for both CO2 and R22 refrigerants, despite the significantly different working pressures. In addition it was addressed that the empirical friction factors were strongly dependent on the relative roughness of leakage channel surface.

  4. Large-Scale candidate gene analysis of spontaneous hepatitis C virus clearance

    PubMed Central

    Mosbruger, Timothy L; Duggal, Priya; Goedert, James J.; Kirk, Gregory D; Hoots, W. Keith; Tobler, Leslie H; Busch, Michael; Peters, Marion G.; Rosen, Hugo R; Thomas, David L; Thio, Chloe L

    2010-01-01

    Human genetic variation is a determinant of recovery from an acute hepatitis C virus (HCV) infection, but, to date, single nucleotide polymorphisms (SNPs) in a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune-response genes are important for HCV clearance by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK and Haploview software packages were used to perform association, permutation, and haplotype analyses stratified by African-American (AA) and European-American (EA) race. Of the 1536 SNPs tested, 1426 were successfully genotyped (92.8%). In AAs, we identified 18 SNPs located in 11 gene regions that were associated with HCV outcome (empirical p-value < 0.01). In EAs, there were 20 SNPs located in eight gene regions associated with HCV outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1 and IL18BP) contained SNPs with empirical p-values < 0.01 in both of the race groups. Conclusion In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified four gene regions that are likely candidates for a role in HCV clearance or persistence in both AAs and EAs. PMID:20331378

  5. Effects of passive smoking on theophylline clearance.

    PubMed

    Matsunga, S K; Plezia, P M; Karol, M D; Katz, M D; Camilli, A E; Benowitz, N L

    1989-10-01

    Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system. PMID:2791443

  6. Statistical Tolerance and Clearance Analysis for Assembly

    NASA Technical Reports Server (NTRS)

    Lee, S.; Yi, C.

    1996-01-01

    Tolerance is inevitable because manufacturing exactly equal parts is known to be impossible. Furthermore, the specification of tolerances is an integral part of product design since tolerances directly affect the assemblability, functionality, manufacturability, and cost effectiveness of a product. In this paper, we present statistical tolerance and clearance analysis for the assembly. Our proposed work is expected to make the following contributions: (i) to help the designers to evaluate products for assemblability, (ii) to provide a new perspective to tolerance problems, and (iii) to provide a tolerance analysis tool which can be incorporated into a CAD or solid modeling system.

  7. Study of blade clearance effects on centrifugal pumps

    NASA Technical Reports Server (NTRS)

    Hoshide, R. K.; Nielson, C. E.

    1972-01-01

    A program of analysis, design, fabrication, and testing has been conducted to develop and experimentally verify analytical models to predict the effects of impeller blade clearance on centrifugal pumps. The effect of tip clearance on pump efficiency, and the relationship between the head coefficient and torque loss with tip clearance was established. Analysis were performed to determine the cost variation in design, manufacture, and test that would occur between unshrouded and shrouded impellers. An impeller, representative of typical rocket engine impellers, was modified by removing its front shroud to permit variation of its blade clearances. It was tested in water with special instrumentation to provide measurements of blade surface pressures during operation. Pump performance data were obtained from tests at various impeller tip clearances. Blade pressure data were obtained at the nominal tip clearance. Comparisons of predicted and measured data are given.

  8. Dynamics analysis of space robot manipulator with joint clearance

    NASA Astrophysics Data System (ADS)

    Zhao, Yang; Bai, Zheng Feng

    2011-04-01

    A computational methodology for analysis of space robot manipulator systems, considering the effects of the clearances in the joint, is presented. The contact dynamics model in joint clearance is established using the nonlinear equivalent spring-damp model and the friction effect is considered using the Coulomb friction model. The space robot system dynamic equation of manipulator with clearance is established. Then the dynamics simulation is presented and the dynamics characteristics of robot manipulator with clearance are analyzed. This work provides a practical method to analyze the dynamics characteristics of space robot manipulator with joint clearance and improves the engineering application. The computational methodology can predict the effects of clearance on space robot manipulator preferably, which is the basis of space robot manipulator design, precision analysis and ground test.

  9. Successful engineering of a highly potent single-chain variable-fragment (scFv) bispecific antibody to target disialoganglioside (GD2) positive tumors

    PubMed Central

    Cheng, Ming; Santich, Brian H.; Xu, Hong; Ahmed, Mahiuddin; Huse, Morgan; Cheung, Nai-Kong V.

    2016-01-01

    ABSTRACT Engineering potent bispecific antibodies from single-chain variable fragments (scFv) remains difficult due to the inherent instability and insufficient binding of scFv's compared to their parental immunoglobulin format. Previously, we described a scFv-based bispecific antibody (scBA) against disialoganglioside (GD2) based on the anti-GD2 murine 5F11-scFv and the anti-CD3 huOKT3-scFv (5F11-scBA). In this study, we substituted the 5F11-scFv with the higher affinity (13-fold) hu3F8-scFv to form hu3F8-scBA. With this modification, hu3F8-scBA redirected T cells to kill GD2(+) cancer cell lines with up to 5,000-fold higher potency (femtomolar EC50) compared with 5F11-scBA (picomolar EC50) in cytotoxicity assays, even against target cells with low GD2 densities. Furthermore, hu3F8-scBA induced stronger T-cell activation than 5F11-scBA, as measured by Ca2+ flux and cytokine release. Additionally, in vivo, hu3F8-scBA suppressed tumor growth and prolonged mice survival much more effectively than 5F11-scBA, in both neuroblastoma and melanoma xenograft models. We conclude that the functional properties of scBA's can be increased substantially by relatively modest increases in antigen affinity. PMID:27471647

  10. Single-dose gentamicin clearance is a predictor of creatinine clearance in spinal man.

    PubMed

    Segal, Jack L; Gilman, Thomas A; Thompson, John F

    2010-01-01

    To identify a radionuclide-free, SCI (spinal cord injury) population-specific method for estimating renal function utilizing the total body clearance of gentamicin as a measure of creatinine clearance (CL(cr)) and glomerular filtration rate (GFR). To incorporate SCI population-specific patient variables into a predictive model for estimating CLcr and GFR. A retrolective study of gentamicin clearance as a measure of GFR in patients with SCI. Each patient had received a single, intravenous dose of gentamicin. Simultaneously, a 24-hour creatinine clearance (CL(cr-24)) was obtained. Experimentally measured total body clearance of a single intravenous administration of gentamicin (CL(gent-iv)) was estimated from PK analyses of gentamicin disposition in patients with SCI. Comparisons were made between CL(gent-iv) and predictors of GFR derived from a SCI population-specific nomogram (SCI-psn), the method of Cockcroft and Gault (C-G), CL(cr-24), and a multiplicative statistical model. A multiplicative model, calculated gentamicin clearance (CL(gent-calc)), that incorporates SCI population-specific characteristics to predict CL(cr-24) and GFR was derived from a multivariate nonlinear regression analysis, and the strengths of association between CL(gent-iv) and CL(gent-calc), and estimates of GFR derived from the method of C-G, SCI-psn, and CL(cr-24) were tested. The best predictive performance was demonstrated for CL(gent-iv) and the multiplicative model, CL(gent-calc), when tested against CL(cr-24) or the SCI-psn, supporting our premise that CL(gent-iv) can be used to estimate GFR in SCI. CL(gent-iv) and CL(gent-calc) outperformed CL(cr-24), the method of C-G, and the SCI-psn as predictors of GFR. The multiplicative model produced estimates of CL(gent-iv) which were more precise and less biased than CL(cr-24), the standard radiation-free predictor of GFR in patients with SCI, the SCI-psn, and the C-G equation. In this preliminary study, the clearance of gentamicin

  11. Deposition and clearance of inhaled particles.

    PubMed Central

    Stuart, B O

    1984-01-01

    Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as governed principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of approximations of the respiratory tract to predict fractional deposition caused by fundamental physical processes of particle impaction, sedimentation, and diffusion. These models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with early and recent experimental studies. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior in the respiratory tract of very fine (less than 0.1 micron) particles requires further investigation. Properties of particle shape, charge and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns; definitive experimental work is needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of differing ventilation techniques with selected inhaled particle sizes holds promise in diagnosis of respiratory tract diseases. Mechanisms of conducting airway and alveolar clearance processes involving the pulmonary macrophage, mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic vessels are discussed. PMID:6376108

  12. Renal Clearance of Mineral Metabolism Biomarkers.

    PubMed

    van Ballegooijen, Adriana J; Rhee, Eugene P; Elmariah, Sammy; de Boer, Ian H; Kestenbaum, Bryan

    2016-02-01

    CKD leads to disturbances in multiple interrelated hormones that regulate bone and mineral metabolism. The renal handling of mineral metabolism hormones in humans is incompletely understood. We determined the single-pass renal clearance of parathyroid hormone, fibroblast growth factor 23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein in 17 participants undergoing simultaneous right and left heart catheterization and estimated associations of eGFR with the renal elimination of metabolites. The mean age ±SD of the study population was 71.4±10.0 years and 11 participants (65%) were male. We found a relatively large mean±SD single-pass renal extraction of parathyroid hormone (44.2%±10.3%) that exceeded the extraction of creatinine (22.1%±7.9%). The proportionate renal extraction of parathyroid hormone correlated with eGFR. The renal extraction of fibroblast growth factor 23 was, on average, lower than that of parathyroid hormone with greater variability across individuals (17.1%±19.5%). There were no differences in the mean concentrations of vitamin D metabolites across the renal vein and artery. In summary, we demonstrate substantial single-pass renal extraction of parathyroid hormone at a rate that exceeds glomerular filtration. Impaired renal clearance of parathyroid hormone may contribute to secondary hyperparathyroidism in CKD. PMID:26047790

  13. ESR measurement of radical clearance in lung of whole mouse

    SciTech Connect

    Takeshita, K.; Utsumi, H.; Hamada, A. )

    1991-06-14

    Clearance of the nitroxide radicals, hydroxy-TEMPO and carboxy-PROxYL, in whole-mouse lung was directly measured by in vivo ESR. After injecting a nitroxide radical, distribution of the nitroxide radical all over the lung was confirmed by ESR imaging. The ESR signal of hydroxy-TEMPO was reduced in the lung and the clearance obeyed first-order kinetics, whereas the signal of carboxy-PROxYL remained constant. Comparison of the clearance rates of live and dead mice indicated the presence of 2 different clearance systems in the lung: loss of its paramagnetism in the lung, and transfer from alveolar to the blood circulation system.

  14. Fuel conservation through active control of rotor clearances

    NASA Technical Reports Server (NTRS)

    Beitler, R. S.; Saunders, A. A.; Wanger, R. P.

    1980-01-01

    Under the NASA-sponsored Energy Efficient Engine (EEE) Project, technology is being developed which will significantly reduce the fuel consumption of turbofan engines for subsonic transport aircraft. One technology concept being pursued is active control of rotor tip clearances. Attention is given to rotor tip clearance considerations and an overview of preliminary study results as well as the General Electric EEE clearance control approach is presented. Finally, potential fuel savings with active control of rotor clearances for a typical EEE mission are predicted.

  15. Developing clinically successful biomedical devices by understanding the pathophysiology of the target tissue: insights from over 25 years at the microscope

    NASA Astrophysics Data System (ADS)

    Thomsen, Sharon L.; Coad, James E.

    2007-02-01

    Volumetric conductive-convective heat sources, microwave and radiofrequency energy sources, high intensity focused ultrasound (HIFU), laser irradiation and other non-ionizing irradiation sources can be used to generate hyperthermic tissue injury in a variety of clinical settings with therapeutic temperature gradients ranging from 40 to over 90°C. On the opposite side, cryotherapy can be used to freeze tissues with negative therapeutic temperature gradients. The development of a successful thermal therapy using any one of these devices requires a precise understanding of the desired clinical end point in terms of 1) diagnosis vs. therapy, 2) cure vs. palliative intent, 3) dysfunctional vs. malignant tissue and 4) long-term monitoring issues. The effects of a specific thermal exposure depend on the architecture of the heat source and overall thermal history. During initial treatment before heat generation or cooling becomes dominant, tissue interactions with the delivered treatment may affect the geometry of the treatment effect and body's healing response. These two parameters are also affected by tissue anatomy, blood supply and protein vs. lipid content. The thermal lesion and final clinical outcome represent the sum of direct primary and secondary short and long term delayed injury. The latter occurs primarily from host responses producing ischemia, inflammation and wound healing followed by possible regeneration and/or scar formation. Once the thermal insult has been deployed, the resulting lesions can be broadly divided into two major zones: 1) a complete tissue ablation with lethal tissue injury closer to the device and 2) a peripheral transition zone of partial injury. Hyperthermic complete ablation zones can have two sub-regions: 1) thermal fixation from direct denaturation of cellular and tissue components and 2) coagulative necrosis due to direct injury and delayed secondary host responses. With a variety of special techniques, direct cellular injury can

  16. Plasmodium Drug Targets Outside the Genetic Control of the Parasite

    PubMed Central

    Sullivan, David J.

    2014-01-01

    Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition. PMID:22973888

  17. Interspecies allometric scaling. Part I: prediction of clearance in large animals.

    PubMed

    Mahmood, I; Martinez, M; Hunter, R P

    2006-10-01

    Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. The knowledge of pharmacokinetics in veterinary species is important for dosage selection, particularly in the treatment of large zoo animal species, such as elephants, giant cats and camels, for which pharmacokinetic data are scant. Therefore, the accuracy in clearance predictions in large animal species, with and without the use of correction factors (rule of exponents), and the impact of species selection in the prediction of clearance in large animal species was examined. Based upon this analysis, it was determined that there is a much larger risk of inaccuracies in the clearance estimates in large animal species when compared with that observed for humans. Unlike in humans, for large animal species, correction factors could not be applied because there was no trend between the exponents of simple allometry and the appropriate correction factor for improving our predictions. Nevertheless, we did see an indication that the exponents of simple allometry may alert us as to when the predicted clearance in the large animal may be underestimated or overpredicted. For example, if a large animal is included in the scaling, the predicted clearance in a large animal should be considered overestimated if the exponent of simple allometry is >1.3. Despite the potential for extrapolation error, the reality is that allometric scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect target animal safety, therapeutic response, or the accuracy of withdrawal time predictions. PMID:16958787

  18. Vaginal chlamydial clearance following primary or secondary infection in mice occurs independently of TNF-α

    PubMed Central

    Kamalakaran, Sangamithra; Chaganty, Bharat K. R.; Gupta, Rishein; Guentzel, M. Neal; Chambers, James P.; Murthy, Ashlesh K.; Arulanandam, Bernard P.

    2013-01-01

    The role of TNF-α in chlamydial clearance is uncertain. Antibody-mediated depletion of TNF-α in mice and guinea pigs has been shown not to significantly affect chlamydial clearance, whereas production of TNF-α in addition to IFN-γ from T cells has been shown to correlate with enhanced clearance. The aim of our study is to evaluate the mechanistic role of TNF-α in clearance of primary and secondary chlamydial infection from the genital tract (GT) using C57BL/6 TNF-α deficient (TNF-α−/−) and wild type (WT) mice. Chlamydial shedding from the lower GT was evaluated following primary and secondary intravaginal challenge. Also, antibody and antigen specific cytokine responses were analyzed from the infected GT and spleens, and oviduct pathology determined to analyze the role of TNF-α in upper GT pathological sequelae. MHC II−/− mice, known to display muted adaptive immune responses and failure to resolve genital chlamydial infections, were used as a negative control. Following both primary and secondary genital chlamydial infection, TNF-α−/− mice exhibited elevated granzyme B production, but similar IFN-γ and antibody responses. Importantly, absence of TNF-α did not significantly alter the resolution of infection. However, TNF-α−/− mice displayed significantly reduced upper genital tract (UGT) pathology compared to WT mice. This study demonstrates mechanistically that optimal chlamydial clearance following primary and secondary chlamydial genital infection can occur in the complete absence of TNF-α, and considered with the reduction of upper GT pathology in TNF-α−/− mice, suggests that targeted induction of anti-chlamydial TNF-α responses by vaccination may be unnecessary, and moreover could be potentially pathogenic. PMID:23483844

  19. Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys.

    PubMed

    Datta-Mannan, Amita; Croy, Johnny E; Schirtzinger, Linda; Torgerson, Stacy; Breyer, Matthew; Wroblewski, Victor J

    2016-07-01

    Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgG-scFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures. PMID:27111637

  20. Differences in amyloid-β clearance across mouse and human blood-brain barrier models: Kinetic analysis and mechanistic modeling

    PubMed Central

    Qosa, Hisham; Abuasal, Bilal S.; Romero, Ignacio A.; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N.; Kaddoumi, Amal

    2014-01-01

    Alzheimer’s disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected 125I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of 125I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of 125I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in 125I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes A

  1. Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling.

    PubMed

    Qosa, Hisham; Abuasal, Bilal S; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N; Kaddoumi, Amal

    2014-04-01

    Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes

  2. Human papillomavirus type 16 viral load measurement as a predictor of infection clearance

    PubMed Central

    Schlecht, Nicolas F.; Ramanakumar, Agnihotram V.; Villa, Luisa L.; Franco, Eduardo L.

    2013-01-01

    Viral load measurements may predict whether human papillomavirus (HPV) type 16 infections may become persistent and eventually lead to cervical lesions. Today, multiple PCR methods exist to estimate viral load. We tested three protocols to investigate viral load as a predictor of HPV clearance. We measured viral load in 418 HPV16-positive cervical smears from 224 women participating in the Ludwig–McGill Cohort Study by low-stringency PCR (LS-PCR) using consensus L1 primers targeting over 40 known HPV types, and quantitative real-time PCR (qRT-PCR) targeting the HPV16 E6 and L1 genes. HPV16 clearance was determined by MY09/11 and PGMY PCR testing on repeated smears collected over 5 years. Correlation between viral load measurements by qRT-PCR (E6 versus L1) was excellent (Spearman’s rank correlation, ρ = 0.88), but decreased for L1 qRT-PCR versus LS-PCR (ρ = 0.61). Viral load by LS-PCR was higher for HPV16 and related types independently of other concurrent HPV infections. Median duration of infection was longer for smears with high copy number by all three PCR protocols (log rank P<0.05). Viral load is inversely related to HPV16 clearance independently of concurrent HPV infections and PCR protocol. PMID:23677791

  3. The biodistribution of gold nanoparticles designed for renal clearance

    NASA Astrophysics Data System (ADS)

    Alric, Christophe; Miladi, Imen; Kryza, David; Taleb, Jacqueline; Lux, François; Bazzi, Rana; Billotey, Claire; Janier, Marc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2013-06-01

    Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate) shell can be established by X-ray imaging (owing to the X-ray absorption of the gold core) and by magnetic resonance imaging (MRI) since the DTDTPA shell was designed for the immobilization of paramagnetic gadolinium ions. However scintigraphy appears better suited for a biodistribution study owing to a great sensitivity. The successful immobilization of radioelements (99mTc, 111In) in the DTDTPA shell, instead of gadolinium ions, renders possible the follow up of Au@DTDTPA by scintigraphy which showed that Au@DTDTPA nanoparticles exhibit a safe behaviour after intravenous injection to healthy rats.Owing to their tunable optical properties and their high absorption cross-section of X- and γ-ray, gold nanostructures appear as promising agents for remotely controlled therapy. Since the efficiency of cancer therapy is not limited to the eradication of the tumour but rests also on the sparing of healthy tissue, a biodistribution study is required in order to determine whether the behaviour of the nanoparticles after intravenous injection is safe (no accumulation in healthy tissue, no uptake by phagocytic cell-rich organs (liver, spleen) and renal clearance). The biodistribution of Au@DTDTPA nanoparticles which are composed of a gold core and a DTDTPA (dithiolated polyaminocarboxylate

  4. The Clearance of Creatinine, Inulin, Para-aminohippurate and Phenosulphothalein in the Cat

    PubMed Central

    Osbaldiston, G. W.; Fuhrman, W.

    1970-01-01

    Endogenous creatinine, inulin, para-amino-hippurate and phenolsulphothalein clearances for healthy cats are presented. The values for inulin and para-aminohippurate clearances (ml/kg/min) are similar to those for the dog. Creatinine clearance was less than inulin clearance values. Pnenolsulphothalein clearance may be a better index of glomerular rather than tubular function in the cat. PMID:4246836

  5. Capacitive measurement of compressor and turbine blade tip to casing running clearance

    SciTech Connect

    Mueller, D.; Mozumdar, S.; Johann, E.; Sheard, A.G.

    1997-10-01

    It is an established fact that the efficiency of a gas turbine engine has an inverse relationship with the clearance between the rotor blades and the casing (Tip Clearance, or TC). TC is an essential measurement during the testing of development engines. While commercial TC measurement systems are available, their applicability to an engine is dictated by engine size, geometry, physical accessibility, and temperature distribution around the measurement region. This paper describes the development of a TC measurement system, based on the capacitive measurement principle, which was undertaken to satisfy the application requirements of a specific class of gas turbine engines. The requirements included a relatively long and flexible cable to route the electrical signals out of the engine. The TC measurement system was successfully used during engine testing and valuable data were obtained.

  6. Interaction between therapeutic interventions for Alzheimer’s disease and physiological Aβ clearance mechanisms

    PubMed Central

    Morrone, Christopher D.; Liu, Mingzhe; Black, Sandra E.; McLaurin, JoAnne

    2015-01-01

    Most therapeutic agents are designed to target a molecule or pathway without consideration of the mechanisms involved in the physiological turnover or removal of that target. In light of this and in particular for Alzheimer’s disease, a number of therapeutic interventions are presently being developed/investigated which target the amyloid-β peptide (Aβ). However, the literature has not adequately considered which Aβ physiological clearance pathways are necessary and sufficient for the effective action of these therapeutics. In this review, we evaluate the therapeutic strategies targeting Aβ presently in clinical development, discuss the possible interaction of these treatments with pathways that under normal physiological conditions are responsible for the turnover of Aβ and highlight possible caveats. We consider immunization strategies primarily reliant on a peripheral sink mechanism of action, small molecules that are reliant on entry into the CNS and thus degradation pathways within the brain, as well as lifestyle interventions that affect vascular, parenchymal and peripheral degradation pathways. We propose that effective development of Alzheimer’s disease therapeutic strategies targeting Aβ peptide will require consideration of the age- and disease-specific changes to endogenous Aβ clearance mechanisms in order to elicit maximal efficacy. PMID:25999850

  7. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo.

    PubMed

    Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos; Schoofs, Till; Sarkar, Debolina; Halper-Stromberg, Ariel; Horwitz, Joshua A; Nogueira, Lilian; Golijanin, Jovana; Gazumyan, Anna; Ravetch, Jeffrey V; Caskey, Marina; Chakraborty, Arup K; Nussenzweig, Michel C

    2016-05-20

    Antiretroviral drugs and antibodies limit HIV-1 infection by interfering with the viral life cycle. In addition, antibodies also have the potential to guide host immune effector cells to kill HIV-1-infected cells. Examination of the kinetics of HIV-1 suppression in infected individuals by passively administered 3BNC117, a broadly neutralizing antibody, suggested that the effects of the antibody are not limited to free viral clearance and blocking new infection but also include acceleration of infected cell clearance. Consistent with these observations, we find that broadly neutralizing antibodies can target CD4(+) T cells infected with patient viruses and can decrease their in vivo half-lives by a mechanism that requires Fcγ receptor engagement in a humanized mouse model. The results indicate that passive immunotherapy can accelerate elimination of HIV-1-infected cells. PMID:27199430

  8. Lactate clearance and metabolic aspects of continuous high-volume hemofiltration

    PubMed Central

    Cheungpasitporn, Wisit; Zand, Ladan; Dillon, John J.; Qian, Qi; Leung, Nelson

    2015-01-01

    Lactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT. PMID:26251702

  9. Improved Flight Test Procedures for Flutter Clearance

    NASA Technical Reports Server (NTRS)

    Lind, Rick C.; Brenner, Martin J.; Freudinger, Lawrence C.

    1997-01-01

    Flight flutter testing is an integral part of flight envelope clearance. This paper discusses advancements in several areas that are being investigated to improve efficiency and safety of flight test programs. Results are presented from recent flight testing of the F/A-18 Systems Research Aircraft. A wingtip excitation system was used to generate aeroelastic response data. This system worked well for many flight conditions but still displayed some anomalies. Wavelet processing is used to analyze the flight data. Filtered transfer functions are generated that greatly improve system identification. A flutter margin is formulated that accounts for errors between a model and flight data. Worst-case flutter margins are computed to demonstrate the flutter boundary may lie closer to the flight envelope than previously estimated. This paper concludes with developments for a distributed flight analysis environment and on-line health monitoring.

  10. Validation of Dose Calculation Codes for Clearance

    SciTech Connect

    Menon, S.; Wirendal, B.; Bjerler, J.; Studsvik; Teunckens, L.

    2003-02-27

    Various international and national bodies such as the International Atomic Energy Agency, the European Commission, the US Nuclear Regulatory Commission have put forward proposals or guidance documents to regulate the ''clearance'' from regulatory control of very low level radioactive material, in order to allow its recycling as a material management practice. All these proposals are based on predicted scenarios for subsequent utilization of the released materials. The calculation models used in these scenarios tend to utilize conservative data regarding exposure times and dose uptake as well as other assumptions as a safeguard against uncertainties. None of these models has ever been validated by comparison with the actual real life practice of recycling. An international project was organized in order to validate some of the assumptions made in these calculation models, and, thereby, better assess the radiological consequences of recycling on a practical large scale.

  11. Capitol Success.

    PubMed

    Sorrel, Amy Lynn

    2015-08-01

    This legislative session, medicine resolved to ensure physicians can give their patients the best care possible. The hard work paid off in significant victories that largely build on the Texas Medical Association's 2013 legislative successes. PMID:26263520

  12. Allometric scaling for predicting human clearance of bisphenol A

    SciTech Connect

    Collet, Séverine H. Picard-Hagen, Nicole Lacroix, Marlène Z. Puel, Sylvie Viguié, Catherine Bousquet-Melou, Alain Toutain, Pierre-Louis Gayrard, Véronique

    2015-05-01

    The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man. - Highlights: • Allometric scaling was used to predict BPA pharmacokinetic parameters in humans. • In all species, BPA plasma clearance approached hepatic blood flow. • Human BPA clearance was estimated to be 1.79 L/min.

  13. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... concerning the foreign intelligence threat, risk of unauthorized technology transfer, type and sensitivity of... SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance. (a... related classified information, or process the facility for a facility clearance. Processing will...

  14. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  15. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  16. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  17. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  18. 20 CFR 655.150 - Interstate clearance of job order.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Interstate clearance of job order. 655.150... job order. (a) SWA posts in interstate clearance system. The SWA must promptly place the job order in... transmit a copy of its active job order to all States listed in the job order as anticipated...

  19. 48 CFR 245.7203 - Assigning plant clearance case numbers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Assigning plant clearance case numbers. 245.7203 Section 245.7203 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Special Instructions 245.7203 Assigning plant clearance case...

  20. Study of global operational needs for mine clearance equipment

    NASA Astrophysics Data System (ADS)

    Blagden, Paddy M.

    2003-09-01

    The Geneva International Centre for Humanitarian Demining studied the needs of landmine clearance groups for equipment to carry out specific functions of mine clearance. This was done on a global level, and useful results were obtained, which will provide the basis for further analysis.

  1. 48 CFR 245.7202 - Establishing a plant clearance case.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Establishing a plant clearance case. 245.7202 Section 245.7202 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Special Instructions 245.7202 Establishing a plant clearance case....

  2. Benefits of Improved HP Turbine Active Clearance Control

    NASA Technical Reports Server (NTRS)

    Ruiz, Rafael; Albers, Bob; Sak, Wojciech; Seitzer, Ken; Steinetz, Bruce M.

    2007-01-01

    As part of the NASA Propulsion 21 program, GE Aircraft Engines was contracted to develop an improved high pressure turbine(HPT) active clearance control (ACC) system. The system is envisioned to minimize blade tip clearances to improve HPT efficiency throughout the engine operation range simultaneously reducing fuel consumption and emissions.

  3. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance. PMID:25683459

  4. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  5. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  6. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  7. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  8. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  9. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  10. 14 CFR 375.24 - Entry and clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Entry and clearance. 375.24 Section 375.24 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS NAVIGATION OF FOREIGN CIVIL AIRCRAFT WITHIN THE UNITED STATES Rules Generally Applicable § 375.24 Entry and clearance. All...

  11. 48 CFR 945.603-70 - Plant clearance function.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Plant clearance function. 945.603-70 Section 945.603-70 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Redistribution, and Disposal of Contractor Inventory 945.603-70 Plant clearance function. If the...

  12. 76 FR 17978 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-31

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security Administration (SSA) publishes a list of information collection packages requiring clearance by the Office of Management and Budget (OMB) in compliance...

  13. 5 CFR 720.307 - Interagency report clearance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Interagency report clearance. 720.307 Section 720.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) AFFIRMATIVE EMPLOYMENT PROGRAMS Disabled Veterans Affirmative Action Program § 720.307 Interagency report clearance. The...

  14. 33 CFR 160.115 - Withholding of clearance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Withholding of clearance. 160.115 Section 160.115 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY PORTS AND WATERWAYS SAFETY-GENERAL Control of Vessel and Facility Operations § 160.115 Withholding of clearance....

  15. 30 CFR 57.19104 - Clearance at shaft stations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance at shaft stations. 57.19104 Section 57.19104 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Personnel Hoisting Shafts § 57.19104 Clearance at...

  16. 30 CFR 56.19104 - Clearance at shaft stations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Clearance at shaft stations. 56.19104 Section 56.19104 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Personnel Hoisting Shafts § 56.19104 Clearance at...

  17. 19 CFR 122.158 - Other entry and clearance requirements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Other entry and clearance requirements. 122.158 Section 122.158 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Flights to and From Cuba § 122.158 Other entry and clearance requirements. All other provisions...

  18. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  19. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  20. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  1. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  2. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  3. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  4. Clearance systems in the brain-implications for Alzheimer disease.

    PubMed

    Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J

    2015-08-01

    Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ. PMID:26195256

  5. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  6. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  7. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  8. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  9. 49 CFR 229.71 - Clearance above top of rail.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Clearance above top of rail. 229.71 Section 229.71....71 Clearance above top of rail. No part or appliance of a locomotive except the wheels, flexible nonmetallic sand pipe extension tips, and trip cock arms may be less than 21/2 inches above the top of rail....

  10. 33 CFR 118.160 - Vertical clearance gauges.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Vertical clearance gauges. 118.160 Section 118.160 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES BRIDGE LIGHTING AND OTHER SIGNALS § 118.160 Vertical clearance gauges. (a) When necessary for reasons of safety of navigation, the...

  11. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  12. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  13. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Clearance of Air Force lands. 644.516 Section... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  14. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Clearance of Air Force lands. 644.516 Section... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  15. 32 CFR 644.516 - Clearance of Air Force lands.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Clearance of Air Force lands. 644.516 Section 644... Excess Land and Improvements § 644.516 Clearance of Air Force lands. The Chief of Engineers has no responsibility for inspecting or clearing excess Air Force land of explosives or chemical/biological...

  16. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  17. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  18. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  19. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  20. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  1. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  2. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Ground clearance: tail rotor guard. 29.411 Section 29.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor...

  3. Clearance systems in the brain—implications for Alzheimer disease

    PubMed Central

    Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J.

    2015-01-01

    Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ. PMID:26195256

  4. 50 CFR 14.52 - Clearance of imported wildlife.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 1 2011-10-01 2011-10-01 false Clearance of imported wildlife. 14.52....52 Clearance of imported wildlife. (a) Except as otherwise provided by this subpart, a Service officer must clear all wildlife imported into the United States prior to release from detention by...

  5. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ground clearance: tail rotor guard. 27.411... System Loads § 27.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor to contact the landing surface during a normal landing. (b) If a tail rotor guard is required to...

  6. 14 CFR 29.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Ground clearance: tail rotor guard. 29.411... System Loads § 29.411 Ground clearance: tail rotor guard. (a) It must be impossible for the tail rotor to contact the landing surface during a normal landing. (b) If a tail rotor guard is required to...

  7. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  8. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  9. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  10. 48 CFR 1432.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... finance office clearance. The CO shall obtain approval of the bureau finance office prior to...

  11. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  12. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  13. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  14. 48 CFR 32.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... finance office clearance. The contracting officer shall obtain the approval of the contract finance...

  15. 48 CFR 832.502-2 - Contract finance office clearance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... finance office clearance. Contracting officers must obtain approval from the DSPE before taking...

  16. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  17. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  18. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  19. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  20. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  1. 32 CFR 644.527 - Recording Statements of Clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Recording Statements of Clearance. 644.527 Section 644.527 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  2. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  3. 32 CFR 644.521 - Limitations on clearance cost.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Limitations on clearance cost. 644.521 Section 644.521 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  4. 32 CFR 644.522 - Clearance of military scrap.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Clearance of military scrap. 644.522 Section 644.522 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal Clearance of Explosive Hazards and Other Contamination from...

  5. Targeting inflammation in pancreatic cancer: Clinical translation.

    PubMed

    Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

    2016-04-15

    Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

  6. Targeting inflammation in pancreatic cancer: Clinical translation

    PubMed Central

    Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

    2016-01-01

    Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

  7. A Microwave Blade Tip Clearance Sensor for Propulsion Health Monitoring

    NASA Technical Reports Server (NTRS)

    Woike, Mark R.; Abdul-Aziz, Ali; Bencic, Timothy J.

    2010-01-01

    Microwave sensor technology is being investigated by the NASA Glenn Research Center as a means of making non-contact structural health measurements in the hot sections of gas turbine engines. This type of sensor technology is beneficial in that it is accurate, it has the ability to operate at extremely high temperatures, and is unaffected by contaminants that are present in turbine engines. It is specifically being targeted for use in the High Pressure Turbine (HPT) and High Pressure Compressor (HPC) sections to monitor the structural health of the rotating components. It is intended to use blade tip clearance to monitor blade growth and wear and blade tip timing to monitor blade vibration and deflection. The use of microwave sensors for this application is an emerging concept. Techniques on their use and calibration needed to be developed. As a means of better understanding the issues associated with the microwave sensors, a series of experiments have been conducted to evaluate their performance for aero engine applications. This paper presents the results of these experiments.

  8. D0 Solenoid Chimney Routing Clearances

    SciTech Connect

    Rucinski, R.; /Fermilab

    1994-02-23

    This engineering note contains information about the measured clearances along the chimney route from the solenoid to the control dewar. This type of information is best conveyed by sketches and a few photos. Twelve photos taken on 2/17/94 are included which gIVe perspective views along the path. The detector was parked in the collision hall on this date. The CF iron was split open to the east and the South EF iron was rolled back. Also the South EndCap Calorimeter was rolled to the south on this day. This allowed personnel access and the photographic opportunity. A full set of raw dimensional sketches are included. These sketches were generated by me using a 25 foot tape measure and a note pad. The sketches are in chronological order with the most recent on top. The first sketch, 5/18/94, describes the 'tightest' location for the upward incline portion of the chimney. The sketches on 2/14/94 thru 2/16/94 are refinements of the early 1992 and 1993 sketches. They pick out quite a bit more detail of specific detector components along the path. The dimensional sketches of 1992 and 1993 gave information in not as much detail and therefore gave a more constrained clearance description. Most of the information of the early sketches was jotted down on the plan view dated 10-29-92. This sketch also had some information lifted from prints which later was superseded by the 1994 sketches. I tried to label components and give views either titled 'Elevation' or 'Plan' which refers to a top view looking down. Also where I could I jotted down direction, ie. South, East etc. Hopefully with a little effort one can decifer it. The curvature of the CC was determined from a three dimensional topographical survey. This survey information is stored in an electronic drawing file 3823.111-ME-317165, 'Solenoid-CC south face 3D shape survey'. The 'z' dimensions for the radial chimney path were picked off this drawing. A curvature was then generated knowing many points by radial and z

  9. Project Success.

    ERIC Educational Resources Information Center

    Meredith, Larry D.

    Project Success consists of after-school, weekend, and summer educational programs geared toward minority and disadvantaged students to increase their numbers seeking postsecondary education from the Meadville, Pennsylvania area. The project is funded primarily through the Edinboro University of Pennsylvania, whose administration is committed to…

  10. Radioaerosol lung clearance in patients with active pulmonary sarcoidosis

    SciTech Connect

    Jacobs, M.P.; Baughman, R.P.; Hughes, J.; Fernandez-Ulloa, M.

    1985-05-01

    Pulmonary radioaerosol clearance rate of /sup 99m/Tc diethylenetriamine pentacetate (DTPA) in 14 patients with untreated sarcoidosis was compared with /sup 67/Ga lung scan and increased lymphocytes in the bronchoalveolar lavage (BAL) fluid. Nine healthy nonsmoking subjects had a mean DTPA clearance rate of 1.18%/min (range, 0.54 to 1.60%/min). Eight of 14 patients with sarcoidosis had clearance rates greater than 1.60%/min. Of those 8 patients with abnormal DTPA clearance, 4 had positive gallium scans, 4 had more than 17% lymphocytes in the BAL fluid, and 3 had both tests positive. To study the cause of abnormal DTPA clearance, 23 subjects (including 3 normal controls, all 14 patients with sarcoidosis, and 6 patients with localized disease on chest roentgenogram) underwent both DTPA clearance studies and BAL for quantitation of the amount of albumin in lung fluid. There was a positive correlation between the rate of DTPA clearance and the albumin concentration in lung fluid (r = 0.87, p less than 0.01).

  11. Distribution and clearance of radioactive aerosol on the nasal mucosa.

    PubMed

    McLean, J A; Bacon, J R; Mathews, K P; Thrall, J H; Banas, J M; Hedden, J; Bayne, N K

    1984-03-01

    The distribution and clearance of aerosolized radioactive technetium 99m pertechnate in physiologic buffered saline was analyzed in four human adult asymptomatic volunteers following delivery into one nostril in the same manner as for nasal challenge testing (i.e., 0.1 ml via a 251 DeVilbiss atomizer powered by a compressor delivering 0.10 +/- 0.01 gm/spray). For comparison, squeeze bottles and spray bottles from commercial sources, a 114 and a 127 DeVilbiss atomizer, and a pipette were employed. Lateral imagery via minicomputer processing was used to determine both distribution and clearance of the radiotracer. The counts after 1 minute were lower following pipette delivery than with the other devices. None yielded discernable , wide-spread distribution of aerosol throughout the nasal cavity. Following delivery from the 251 atomizer, mean clearance at 17 minutes was 60.0%. Similar clearance rates were obtained with the other spraying methods except for lower values with the squeeze bottle. Analysis of six hour clearance studies by linear regression showed a relatively rapid initial phase, which is probably due largely to mucociliary clearance, and a prolonged late phase related to the very slow disappearance of residual material located far anteriorly in the nose. Achieving good initial retention and rapid clearance of material deposited anteriorly in the nose are desirable attributes of devices employed for administering materials intranasally. PMID:6328631

  12. Lung Edema Clearance: Relevance to Patients with Lung Injury

    PubMed Central

    Azzam, Zaher S.; Sznajder, Jacob I.

    2015-01-01

    Pulmonary edema clearance is necessary for patients with lung injury to recover and survive. The mechanisms regulating edema clearance from the lungs are distinct from the factors contributing edema formation during injury. Edema clearance is effected via vectorial transport of Na+ out of the airspaces which generates an osmotic gradient causing water to follow the gradient out of the cells. This Na+ transport across the alveolar epithelium is mostly effected via apical Na+ and chloride channels and basolateral Na,K-ATPase. The Na,K-ATPase pumps Na+ out of the cell and K+ into the cell against their respective gradients in an ATP-consuming reaction. Two mechanisms contribute to the regulation of the Na,K-ATPase activity:recruitment of its subunits from intracellular compartments into the basolateral membrane, and transcriptional/translational regulation. Na,K-ATPase activity and edema clearance are increased by catecholamines, aldosterone, vasopressin, overexpression of the pump genes, and others. During lung injury, mechanisms regulating edema clearance are inhibited by yet unclear pathways. Better understanding of the mechanisms that regulate pulmonary edema clearance may lead to therapeutic interventions that counterbalance the inhibition of edema clearance during lung injury and improve the lungs’ ability to clear fluid, which is crucial for patient survival. PMID:26241220

  13. Dynamic modelling and experimental study of cantilever beam with clearance

    NASA Astrophysics Data System (ADS)

    Li, B.; Jin, W.; Han, L.; He, Z.

    2012-05-01

    Clearances occur in almost all mechanical systems, typically such as the clearance between slide plate of gun barrel and guide. Therefore, to study the clearances of mechanisms can be very important to increase the working performance and lifetime of mechanisms. In this paper, rigid dynamic modelling of cantilever with clearance was done according to the subject investigated. In the rigid dynamic modelling, clearance is equivalent to the spring-dashpot model, the impact of beam and boundary face was also taken into consideration. In ADAMS software, the dynamic simulation was carried out according to the model above. The software simulated the movement of cantilever with clearance under external excitation. Research found: When the clearance is larger, the force of impact will become larger. In order to study how the stiffness of the cantilever's supporting part influences natural frequency of the system, A Euler beam which is restricted by a draught spring and a torsion spring at its end was raised. Through numerical calculation, the relationship between natural frequency and stiffness was found. When the value of the stiffness is close to the limit value, the corresponding boundary condition is illustrated. An ADAMS experiment was carried out to check the theory and the simulation.

  14. Inter-individual variation in midazolam clearance in children

    PubMed Central

    Altamimi, Mohammed I; Sammons, Helen; Choonara, Imti

    2015-01-01

    Objectives To determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation. Methods A systematic literature review was performed to identify papers describing the clearance of midazolam in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL and Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. Results 25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%–170%) than non-critically ill patients (13%–54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%–106% in preterm neonates, 18%–73% in term neonates, 31%–130% in infants, 21%–170% in children and 47%–150% in adolescents. The mean clearance was higher in children (1.1–16.7 mL/min/kg) than in neonates (0.78–2.5 mL/min/kg). Conclusions Large inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents. PMID:25281734

  15. Hepatic transcriptome analysis of hepatitis C virus infection in chimpanzees defines unique gene expression patterns associated with viral clearance.

    PubMed

    Nanda, Santosh; Havert, Michael B; Calderón, Gloria M; Thomson, Michael; Jacobson, Christian; Kastner, Daniel; Liang, T Jake

    2008-01-01

    Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV) infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3) and cytotoxic granule-associated RNA binding protein (TIA1), associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a "danger signal" leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection. PMID:18927617

  16. Immunotherapy for the treatment of Alzheimer’s disease: amyloid-β or tau, which is the right target?

    PubMed Central

    Castillo-Carranza, Diana L; Guerrero-Muñoz, Marcos J; Kayed, Rakez

    2014-01-01

    Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ) protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions. PMID:27471697

  17. Aerosol Medications for Treatment of Mucus Clearance Disorders.

    PubMed

    Rubin, Bruce K

    2015-06-01

    Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive lung disease, leading to an ineffective cough. There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance. PMID:26070577

  18. Time-of-Flight Tip-Clearance Measurements

    NASA Technical Reports Server (NTRS)

    Dhadwal, H. S.; Kurkov, A. P.; Janetzke, D. C.

    1999-01-01

    In this paper a time-of-flight probe system incorporating the two integrated fiber optic probes which are tilted equally relative to the probe holder centerline, is applied for the first time to measure the tip clearance of an advanced fan prototype. Tip clearance is largely independent of the signal amplitude and it relies on timing measurement. This work exposes optical effects associated with the fan blade stagger angle that were absent during the original spin-rig experiment on the zero stagger rotor. Individual blade tip clearances were measured with accuracy of +/- 127-mm (+/- 0.005-in). Probe features are discussed and improvements to the design are suggested.

  19. Preliminary Diffusive Clearance of Silicon Nanopore Membranes in a Parallel Plate Configuration for Renal Replacement Therapy.

    PubMed

    Kim, Steven; Heller, James; Iqbal, Zohora; Kant, Rishi; Kim, Eun Jung; Durack, Jeremy; Saeed, Maythem; Do, Loi; Hetts, Steven; Wilson, Mark; Brakeman, Paul; Fissell, William H; Roy, Shuvo

    2016-01-01

    Silicon nanopore membranes (SNMs) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here, we present an initial evaluation of the SNM's mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200 ml/min) and pressures (1,448 mm Hg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25 ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4 hours in an extracorporeal porcine model. The pressure drop across the flow cell was 4.6 mm Hg at 200 ml/min. Mechanical testing showed that SNM could withstand up to 775.7 mm Hg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extracorporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1-fold increase and 1.8-fold increase over polyethylene glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy. PMID:26692401

  20. A novel approach to achieving modular retrovirus clearance for a parvovirus filter.

    PubMed

    Stuckey, Juliana; Strauss, Daniel; Venkiteshwaran, Adith; Gao, Jinxin; Luo, Wen; Quertinmont, Michelle; O'Donnell, Sean; Chen, Dayue

    2014-01-01

    Viral filtration is routinely incorporated into the downstream purification processes for the production of biologics produced in mammalian cell cultures (MCC) to remove potential viral contaminants. In recent years, the use of retentive filters designed for retaining parvovirus (~20 nm) has become an industry standard in a conscious effort to further improve product safety. Since retentive filters remove viruses primarily by the size exclusion mechanism, it is expected that filters designed for parvovirus removal can effectively clear larger viruses such as retroviruses (~100 nm). In an attempt to reduce the number of viral clearance studies, we have taken a novel approach to demonstrate the feasibility of claiming modular retrovirus clearance for Asahi Planova 20N filters. Porcine parvovirus (PPV) and xenotropic murine leukemia virus (XMuLV) were co-spiked into six different feedstreams and then subjected to laboratory scale Planova 20N filtration. Our results indicate that Planova 20N filters consistently retain retroviruses and no retrovirus has ever been detected in the filtrates even when significant PPV breakthrough is observed. Based on the data from multiple in-house viral validation studies and the results from the co-spiking experiments, we have successfully claimed a modular retrovirus clearance of greater than 6 log10 reduction factors (LRF) to support clinical trial applications in both USA and Europe. PMID:24123923

  1. Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages.

    PubMed

    Petrusca, Daniela N; Gu, Yuan; Adamowicz, Jeremy J; Rush, Natalia I; Hubbard, Walter C; Smith, Patricia A; Berdyshev, Evgeni V; Birukov, Konstantin G; Lee, Chao-Hung; Tuder, Rubin M; Twigg, Homer L; Vandivier, R William; Petrache, Irina

    2010-12-17

    A decreased clearance of apoptotic cells (efferocytosis) by alveolar macrophages (AM) may contribute to inflammation in emphysema. The up-regulation of ceramides in response to cigarette smoking (CS) has been linked to AM accumulation and increased detection of apoptotic alveolar epithelial and endothelial cells in lung parenchyma. We hypothesized that ceramides inhibit the AM phagocytosis of apoptotic cells. Release of endogenous ceramides via sphingomyelinase or exogenous ceramide treatments dose-dependently impaired apoptotic Jurkat cell phagocytosis by primary rat or human AM, irrespective of the molecular species of ceramide. Similarly, in vivo augmentation of lung ceramides via intratracheal instillation in rats significantly decreased the engulfment of instilled target apoptotic thymocytes by resident AM. The mechanism of ceramide-induced efferocytosis impairment was dependent on generation of sphingosine via ceramidase. Sphingosine treatment recapitulated the effects of ceramide, dose-dependently inhibiting apoptotic cell clearance. The effect of ceramide on efferocytosis was associated with decreased membrane ruffle formation and attenuated Rac1 plasma membrane recruitment. Constitutively active Rac1 overexpression rescued AM efferocytosis against the effects of ceramide. CS exposure significantly increased AM ceramides and recapitulated the effect of ceramides on Rac1 membrane recruitment in a sphingosine-dependent manner. Importantly, CS profoundly inhibited AM efferocytosis via ceramide-dependent sphingosine production. These results suggest that excessive lung ceramides may amplify lung injury in emphysema by causing both apoptosis of structural cells and inhibition of their clearance by AM. PMID:20956540

  2. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

    PubMed Central

    Keaney, James; Walsh, Dominic M.; O’Malley, Tiernan; Hudson, Natalie; Crosbie, Darragh E.; Loftus, Teresa; Sheehan, Florike; McDaid, Jacqueline; Humphries, Marian M.; Callanan, John J.; Brett, Francesca M.; Farrell, Michael A.; Humphries, Peter; Campbell, Matthew

    2015-01-01

    The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain. PMID:26491725

  3. Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper.

    PubMed

    Musashe, Derek T; Purice, Maria D; Speese, Sean D; Doherty, Johnna; Logan, Mary A

    2016-08-16

    Neuronal injury triggers robust responses from glial cells, including altered gene expression and enhanced phagocytic activity to ensure prompt removal of damaged neurons. The molecular underpinnings of glial responses to trauma remain unclear. Here, we find that the evolutionarily conserved insulin-like signaling (ILS) pathway promotes glial phagocytic clearance of degenerating axons in adult Drosophila. We find that the insulin-like receptor (InR) and downstream effector Akt1 are acutely activated in local ensheathing glia after axotomy and are required for proper clearance of axonal debris. InR/Akt1 activity, it is also essential for injury-induced activation of STAT92E and its transcriptional target draper, which encodes a conserved receptor essential for glial engulfment of degenerating axons. Increasing Draper levels in adult glia partially rescues delayed clearance of severed axons in glial InR-inhibited flies. We propose that ILS functions as a key post-injury communication relay to activate glial responses, including phagocytic activity. PMID:27498858

  4. Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen

    PubMed Central

    Javid, Ashkan; Zlotnikov, Nataliya; Pětrošová, Helena; Tang, Tian Tian; Zhang, Yang; Bansal, Anil K.; Ebady, Rhodaba; Parikh, Maitry; Ahmed, Mijhgan; Sun, Chunxiang; Newbigging, Susan; Kim, Yae Ram; Santana Sosa, Marianna; Glogauer, Michael

    2016-01-01

    Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted. PMID:27340827

  5. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain

    PubMed Central

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-01

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson’s disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases. PMID:26792101

  6. Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation

    PubMed Central

    2013-01-01

    The deposition, clearance and translocation of europium-doped gadolinium oxide nanoparticles in a mouse lung were investigated experimentally. Nanoparticles were synthesized by spray flame pyrolysis. The particle size, crystallinity and surface properties were characterized. Following instillation, the concentrations of particles in organs were determined with inductively coupled plasma mass spectrometry. The protein corona coating the nanoparticles was found to be similar to the coating on more environmentally relevant nanoparticles such as iron oxide. Measurements of the solubility of the nanoparticles in surrogates of biological fluids indicated very little propensity for dissolution, and the elemental ratio of particle constituents did not change, adding further support to the contention that intact nanoparticles were measured. The particles were intratracheally instilled into the mouse lung. After 24 hours, the target organs were harvested, acid digested and the nanoparticle mass in each organ was measured by inductively coupled plasma mass spectrometry (ICP-MS). The nanoparticles were detected in all the studied organs at low ppb levels; 59% of the particles remained in the lung. A significant amount of particles was also detected in the feces, suggesting fast clearance mechanisms. The nanoparticle system used in this work is highly suitable for quantitatively determining deposition, transport and clearance of nanoparticles from the lung, providing a quantified measure of delivered dose. PMID:23305071

  7. Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.

    PubMed

    Javid, Ashkan; Zlotnikov, Nataliya; Pětrošová, Helena; Tang, Tian Tian; Zhang, Yang; Bansal, Anil K; Ebady, Rhodaba; Parikh, Maitry; Ahmed, Mijhgan; Sun, Chunxiang; Newbigging, Susan; Kim, Yae Ram; Santana Sosa, Marianna; Glogauer, Michael; Moriarty, Tara J

    2016-01-01

    Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted. PMID:27340827

  8. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    PubMed

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-01

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases. PMID:26792101

  9. Metabolic clearance rate and urinary clearance of purified beta-core

    SciTech Connect

    Wehmann, R.E.; Blithe, D.L.; Flack, M.R.; Nisula, B.C. )

    1989-09-01

    We injected a highly purified preparation of the beta-core molecule, a fragment of hCG beta excreted in pregnancy urine, into five men and three women to determine its kinetic parameters, MCR, and urinary clearance. The beta-core molecule was distributed in an initial volume (1950 +/- 156 (mean +/- SEM) mL/m2 body surface area) approximately equal to the estimated plasma volume. Its disappearance was multiexponential on a semilogarithmic plot, with a rapid phase t1/2 of 3.5 +/- 0.7 min and a slow phase t1/2 of 22.4 +/- 4.2 min. The transit time (the mean time spent by a molecule of beta-core in transit) was 20.6 +/- 2.1 min. The MCR was 192.0 +/- 8.0 mL/min.m2 body surface area. About 5% of the injected dose of beta-core was excreted into the urine in the first 30 min after injection, and low levels of excretion persisted for up to 7 days. The urinary clearance rate of beta-core was 13.7 +/- 1.4 mL/min.m2, accounting for about 8% of the elimination of beta-core from the plasma. The beta-core immunoreactivity in serum and urine was characterized by gel filtration and three independent RIA systems to show that its properties were indistinguishable from those of the injected beta-core. Serum levels of beta-core in pregnant women were less than 0.2 ng/mL, while the amounts excreted in their urine were as much as 5 mg/day. Based on these clearance parameters of beta-core in normal subjects, less than 0.2% of the beta-core excreted in pregnancy urine is derived by urinary clearance of plasma beta-core. Therefore, more than 99% of the beta-core excreted in pregnancy urine is derived from beta-core in a compartment separate from plasma. In particular, these data indicate that there is relatively little placental secretion of beta-core into plasma and that placental secretion does not account for the vast majority of beta-core in pregnancy urine.

  10. Direct measurement of first-pass ileal clearance of a bile acid in humans

    SciTech Connect

    Galatola, G.; Jazrawi, R.P.; Bridges, C.; Joseph, A.E.; Northfield, T.C. )

    1991-04-01

    The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%).

  11. Tissue-Protective Effects of NKG2A in Immune-Mediated Clearance of Virus Infection

    PubMed Central

    DeBerge, Matthew P.; Ruby, Jessica A.; Liu, Jun; Schneider, Mark J.; Wang, Yan; Hahn, Young S.; Enelow, Richard I.

    2014-01-01

    Virus infection triggers a CD8+ T cell response that aids in virus clearance, but also expresses effector functions that may result in tissue injury. CD8+ T cells express a variety of activating and inhibiting ligands, though regulation of the expression of inhibitory receptors is not well understood. The ligand for the inhibitory receptor, NKG2A, is the non-classical MHC-I molecule Qa1b, which may also serve as a putative restricting element for the T cell receptors of purported regulatory CD8+ T cells. We have previously shown that Qa1b-null mice suffer considerably enhanced immunopathologic lung injury in the context of CD8+ T cell-mediated clearance of influenza infection, as well as evidence in a non-viral system that failure to ligate NKG2A on CD8+ effector T cells may represent an important component of this process. In this report, we examine the requirements for induction of NKG2A expression, and show that NKG2A expression by CD8+ T cells occurs as a result of migration from the MLN to the inflammatory lung environment, irrespective of peripheral antigen recognition. Further, we confirmed that NKG2A is a mediator in limiting immunopathology in virus infection using mice with a targeted deletion of NKG2A, and infecting the mutants with two different viruses, influenza and adenovirus. In neither infection is virus clearance altered. In influenza infection, the enhanced lung injury was associated with increased chemoattractant production, increased infiltration of inflammatory cells, and significantly enhanced alveolar hemorrhage. The primary mechanism of enhanced injury was the loss of negative regulation of CD8+ T cell effector function. A similar effect was observed in the livers of mutant mice infected intravenously with adenovirus. These results demonstrate the immunoregulatory role of CD8+ NKG2A expression in virus infection, which negatively regulates T cell effector functions and contributes to protection of tissue integrity during virus clearance

  12. Inflammation and clearance of Chlamydia trachomatis in enteric and nonenteric mucosae.

    PubMed

    Igietseme, J U; Portis, J L; Perry, L L

    2001-03-01

    Immunization(s) fostering the induction of genital mucosa-targeted immune effectors is the goal of vaccines against sexually transmitted diseases. However, it is uncertain whether vaccine administration should be based on the current assumptions about the common mucosal immune system. We investigated the relationship between mucosal sites of infection, infection-induced inflammation, and immune-mediated bacterial clearance in mice using the epitheliotropic pathogen Chlamydia trachomatis. Chlamydial infection of the conjunctival, pulmonary, or genital mucosae stimulated significant changes in tissue architecture with dramatic up-regulation of the vascular addressin, VCAM, a vigorous mixed-cell inflammatory response with an influx of alpha4beta1+ T cells, and clearance of bacteria within 30 days. Conversely, intestinal mucosa infection was physiologically inapparent, with no change in expression of the local MAdCAM addressin, no VCAM induction, no histologically detectable inflammation, and no tissue pathology. Microbial clearance was complete within 60 days in the small intestine but bacterial titers remained at high levels for at least 8 months in the large intestine. These findings are compatible with the notion that VCAM plays a functional role in recruiting cells to inflammatory foci, and its absence from the intestinal mucosa contributes to immunologic homeostasis at that site. Also, expression of type 1 T cell-mediated immunity to intracellular Chlamydia may exhibit tissue-specific variation, with the rate and possibly the mechanism(s) of clearance differing between enteric and nonenteric mucosae. The implications of these data for the common mucosal immune system and the delivery of vaccines against mucosal pathogens are discussed. PMID:11179361

  13. Effect of mouse strain as a background for Alzheimer’s disease models on the clearance of amyloid-β

    PubMed Central

    Qosa, Hisham; Kaddoumi, Amal

    2016-01-01

    Novel animal models of Alzheimer’s disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species. Here, we used the brain clearance index (BCI) method to investigate the effect of strain differences on the clearance of amyloid β (Aβ) from the brains of four mouse strains. These mouse strains, namely C57BL/6, FVB/N, BALB/c and SJL/J, are widely used as a background for the development of AD mouse models. Findings showed that while Aβ clearance across the blood-brain barrier (BBB) was comparable between the 4 strains, levels of LRP1, an Aβ clearance protein, was significantly lower in SJL/J mice compared to other mouse strains. Furthermore, these mouse strains showed a significantly different response to rifampicin treatment with regard to Aβ clearance and effect on brain level of its clearance-related proteins. Our results provide for the first time an evidence for strain differences that could affect ability of AD mouse models to recapitulate response to a drug, and opens a new research avenue that requires further investigation to successfully develop mouse models that could simulate clinically important phenotypic characteristics of AD.

  14. Intraarticular volume and clearance in human synovial effusions

    SciTech Connect

    Wallis, W.J.; Simkin, P.A.; Nelp, W.B.; Foster, D.M.

    1985-04-01

    Intraarticular volumes were measured by radiolabeled albumin (RISA) distribution in chronic knee effusions from 11 rheumatoid arthritis patients and 9 osteoarthritis patients. Volumes of synovial fluid obtained at joint aspiration were substantially less than those found by RISA dilution. Up to 24 hours was needed for full distribution of RISA throughout the intraarticular compartment. Measured 123I and RISA radioactivity over the knee described monoexponential rate constants, lambda (minute-1). The clearance of 123I and RISA from synovial effusions was derived by the formulation volume (ml) X lambda (minute-1) = clearance (ml/minute). RISA clearance in rheumatoid effusions was significantly greater than that found in osteoarthritis effusions. Intraarticular volume and isotope clearance were easily quantified and provide measures for further evaluating the microvascular physiology of synovial effusions.

  15. 54. CLEARANCE OF SITE PRIOR TO CONSTRUCTION OF BREAKER BUILDING, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    54. CLEARANCE OF SITE PRIOR TO CONSTRUCTION OF BREAKER BUILDING, AND CONSTRUCTION OF EMBANKMENT FOR RAILROAD SPUR. c.1898 (AKZO No. A-3) - Avery Island Salt Works, Akzo Salt Incorporated, Avery Island, Iberia Parish, LA

  16. [Bromsulphalein clearance in persons in occupational contact with pesticides].

    PubMed

    Mechkov, G; Petkova, V; Zakhariev, N

    1987-01-01

    In 46 persons (sprayers, disinfectors, technicians of the agricultural aviation) the bromsulphalein clearance is traced, during the active work season with pesticides, after the method of Caroly, Nys and Alliot. It is established, that the mean value of bromsulphalein clearance (8.91%) is lower than that of the referent group healthy persons (14.5%). In 14 (31.34%) of the examined the values of the clearance are under 10%. The changes of the last do not correlate closely to other indices of the liver function. As an explanation of the results the authors presuppose general pathogenetic relations between the metabolism of pesticides and of bromsulphalein in the liver cell, with inclusion of glutathione-S-transferase systems. The study allows to give a practical conclusion for the meaning of the bromsulphalein clearance and assessment of the pesticides effect in persons who are in professional contact with them. PMID:3441475

  17. 75 FR 37518 - Agency Information Collection Activities: Emergency Clearance Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-29

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Agency Information Collection Activities: Emergency Clearance Request The Social Security... technology. Mail, e-mail, or fax your comments and recommendations on the information collection to the...

  18. Mucociliary clearance mechanism in smoking and nonsmoking normal subjects

    SciTech Connect

    Isawa, T.; Teshima, T.; Hirano, T.; Ebina, A.; Konno, K.

    1984-03-01

    Mucociliary clearance mechanisms were evaluated in 17 normal subjects visually and qualitatively by radioaerosol inhalation cinescintigraphy of the lung, and quantitatively by calculating the following indices: (a) overall or regional lung retention ratio; (b) airway deposition ratio; (c) airway retention ratio; (d) airway clearance efficiency; and (e) alveolar deposition ratio. The inhaled aerosol deposited homogeneously throughout the lungs, and mucus transport was always cephalad in direction and constant in velocity, although a temporary stasis of mucus was seen in smokers. Overall lung retention ratio was significantly smaller and airway deposition ratio was significantly larger in the smokers than in nonsmokers, but there was no difference between the groups in airway retention ratio or airway clearance efficiency. There was an inverse relationship between alveolar deposition ratio and cigarette consumption. Mucociliary clearance mechanisms were well maintained in the normal subjects, but in the smokers inhaled aerosol tended to deposit more proximally.

  19. 33 CFR 151.1508 - Revocation of clearance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... BALLAST WATER Ballast Water Management for Control of Nonindigenous Species in the Great Lakes and Hudson River § 151.1508 Revocation of clearance. A COTP may request the District Director of Customs...

  20. 33 CFR 151.1508 - Revocation of clearance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... BALLAST WATER Ballast Water Management for Control of Nonindigenous Species in the Great Lakes and Hudson River § 151.1508 Revocation of clearance. A COTP may request the District Director of Customs...

  1. 33 CFR 151.1508 - Revocation of clearance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... BALLAST WATER Ballast Water Management for Control of Nonindigenous Species in the Great Lakes and Hudson River § 151.1508 Revocation of clearance. A COTP may request the District Director of Customs...

  2. Further Characterization of an Active Clearance Control Concept

    NASA Technical Reports Server (NTRS)

    Taylor, Shawn C.; Steinetz, Bruce M.; Oswald, Jay J.

    2007-01-01

    A new test chamber and precision hydraulic actuation system were incorporated into an active clearance control (ACC) test rig at NASA Glenn Research Center. Using the improved system, a fast-acting, mechanically-actuated, ACC concept was evaluated at engine simulated temperatures and pressure differentials up to 1140 F and 120 psig, on the basis of secondary seal leakage and kinematic controllability. During testing, the ACC concept tracked a simulated flight clearance transient profile at 1140 F, 120 psig, with a maximum error of only 0.0012 in. Comparison of average dynamic leakage of the system with average static leakage did not show significant differences between the two operating conditions. Calculated effective clearance values for the rig were approximately 0.0002 in. at 120 psig, well below the industry specified effective clearance threshold of 0.001 in.

  3. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  4. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  5. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  6. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  7. 32 CFR 644.517 - Clearance of Army lands.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Clearance, the following information will be furnished to the DE upon completion of the neutralization: (a) Records of the neutralization work performed, including statement of methods employed. (b) List...

  8. IFNL4 affects clearance of hepatitis C virus

    Cancer.gov

    Scientists have discovered a new human interferon gene, Interferon Lambda 4 (IFNL4), that affects clearance of the hepatitis C virus. They also identified an inherited genetic variant within IFNL4 that predicts how people respond to treatment for hepatit

  9. Clearance detector and method for motion and distance

    DOEpatents

    Xavier, Patrick G.

    2011-08-09

    A method for correct and efficient detection of clearances between three-dimensional bodies in computer-based simulations, where one or both of the volumes is subject to translation and/or rotations. The method conservatively determines of the size of such clearances and whether there is a collision between the bodies. Given two bodies, each of which is undergoing separate motions, the method utilizes bounding-volume hierarchy representations for the two bodies and, mappings and inverse mappings for the motions of the two bodies. The method uses the representations, mappings and direction vectors to determine the directionally furthest locations of points on the convex hulls of the volumes virtually swept by the bodies and hence the clearance between the bodies, without having to calculate the convex hulls of the bodies. The method includes clearance detection for bodies comprising convex geometrical primitives and more specific techniques for bodies comprising convex polyhedra.

  10. Numerical simulation of tip clearance effects in turbomachinery

    SciTech Connect

    Basson, A.; Lakshminarayana, B.

    1995-07-01

    The numerical formulation developed here includes an efficient grid generation scheme, particularly suited to computational grids for the analysis of turbulent turbomachinery flows and tip clearance flows, and a semi-implicit, pressure-based computational fluid dynamics scheme that directly includes artificial dissipation,a nd is applicable to both viscous and inviscid flows. The value of this artificial dissipation is optimized to achieve accuracy and convergency in the solution. The numerical model is used to investigate the structure of tip clearance flows in a turbine nozzle. The structure of leakage flow is captured accurately, including blade-to-blade variation of all three velocity components, pitch and yaw angles, losses and blade static pressures in the tip clearance region. The simulation also includes evaluation of such quantities the spanwise extent affected by the leakage flow. It is demonstrated, through optimization of grid size and artificial dissipation, that the tip clearance flow field can be captured accurately.

  11. Antibody-Mediated Clearance of Alphavirus Infection from Neurons

    NASA Astrophysics Data System (ADS)

    Levine, Beth; Hardwick, J. Marie; Trapp, Bruce D.; Crawford, Thomas O.; Bollinger, Robert C.; Griffin, Diane E.

    1991-11-01

    Humoral immunity is important for protection against viral infection and neutralization of extracellular virus, but clearance of virus from infected tissues is thought to be mediated solely by cellular immunity. However, in a SCID mouse model of persistent alphavirus encephalomyelitis, adoptive transfer of hyperimmune serum resulted in clearance of infectious virus and viral RNA from the nervous system, whereas adoptive transfer of sensitized T lymphocytes had no effect on viral replication. Three monoclonal antibodies to two different epitopes on the E2 envelope glycoprotein mediated viral clearance. Treatment of alphavirus-infected primary cultured rat neurons with these monoclonal antibodies to E2 resulted in decreased viral protein synthesis, followed by gradual termination of mature infectious virion production. Thus, antibody can mediate clearance of alphavirus infection from neurons by restricting viral gene expression.

  12. High Temperature Evaluation of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Taylor, Shawn C.; Steinetz, Bruce M.; Oswald, Jay J.

    2006-01-01

    A mechanically actuated blade tip clearance control concept was evaluated in a nonrotating test rig to quantify secondary seal leakage at elevated temperatures. These tests were conducted to further investigate the feasibility of actively controlling the clearance between the rotor blade tips and the surrounding shroud seal in the high pressure turbine (HPT) section of a turbine engine. The test environment simulates the state of the back side of the HPT shroud seal with pressure differentials as high as 120 psig and temperatures up to 1000 F. As expected, static secondary seal leakage decreased with increasing temperature. At 1000 F, the test rig's calculated effective clearance (at 120 psig test pressure) was 0.0003 in., well within the industry specified effective clearance goal.

  13. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

    PubMed Central

    Polito, Vinicia A; Li, Hongmei; Martini-Stoica, Heidi; Wang, Baiping; Yang, Li; Xu, Yin; Swartzlander, Daniel B; Palmieri, Michela; di Ronza, Alberto; Lee, Virginia M-Y; Sardiello, Marco; Ballabio, Andrea; Zheng, Hui

    2014-01-01

    Accumulating evidence implicates impairment of the autophagy-lysosome pathway in Alzheimer's disease (AD). Recently discovered, transcription factor EB (TFEB) is a molecule shown to play central roles in cellular degradative processes. Here we investigate the role of TFEB in AD mouse models. In this study, we demonstrate that TFEB effectively reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy with no detectable adverse effects when expressed in wild-type mice. TFEB specifically targets hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving normal Tau intact. We provide in vitro evidence that this effect requires lysosomal activity and we identify phosphatase and tensin homolog (PTEN) as a direct target of TFEB that is required for TFEB-dependent aberrant Tau clearance. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species makes it an attractive therapeutic target for treating diseases of tauopathy including AD. PMID:25069841

  14. Radioaerosol clearance to monitor effects of ozone on lung permeability

    SciTech Connect

    Webb, D.A.; Utell, M.J.; Bauer, M.A.; Banko, T.M.; Waldman, D.L.; Morrow, P.E.; Hyde, R.W.

    1985-05-01

    The Tc-99m DTPA aerosol clearance procedure was used to investigate the effects of low level ozone inhalation on lung permeability. Total and regional lung clearance was determined by scintillation camera imaging of 15 adult subjects presenting no history of lung disease using a radioaerosol with an aerodynamic diameter 0.5 ..mu..m(sigmag=1.50). Pulmonary function measurements and the radioaerosol procedure were conducted in each patient on at least two separate occasions. FVC, FEVl and airway resistance was measured pre and post monitored breathing of room air (30 min) and a subsequent aerosol clearance procedure was conducted as a baseline study; the same procedures were repeated after three or more days with 0.5 ppm ozone substituted for room air. The major observations from the clearance studies and the pulmonary function tests include: 1) no significant changes were detected between the baseline and ozone pulmonary function tests, 2) ROI analyses of the 30 min clearance data show no significant changes in the average Tc-99m DTPA clearance between the baseline room air (t1/2=85+-30 min) and ozone (t1/2=83+-24min) inhalation studies, and, 3) despite consistent average clearance rates, 7/15 subjects showed large changes in clearance (..delta..=24-72 min) and functional mapping showed major shifts in distribution in 5/15 subjects after ozone inhalation. The apparent high sensitivity, yet somewhat disparate observations, support the need of further investigation of factors influencing radioaerosol for the study of lung epithelial permeability.

  15. Measuring Motor-Shaft Clearance And Wobble During Operation

    NASA Technical Reports Server (NTRS)

    Chern, Engmin James

    1996-01-01

    Noncontact proximity sensor, preferably eddy-current liftoff probe, provides realtime measurement of distance and small variations of distance between two mechanical components designed to be maintained at precise, fixed distance. In particular, system intended for use in measuring lateral clearance and variations in lateral clearance (wobble) of motor shaft relative to motor housing while shaft turning. Provides early indication of wear in motor bearings. Rate of rotation also measured.

  16. Early Agriculture: Land Clearance and Climate Effects

    NASA Astrophysics Data System (ADS)

    Ruddiman, W. F.

    2013-12-01

    inception. Well-dated high-resolution CO2 (and CH4) records from ice cores show gas decreases that correlate closely with major pandemics and civil strife, but show little if any link to temperature or precipitation trends. One significant (and intriguing) discrepancy with the original hypothesis remains. Most of the CO2 rise occurred between 6000 and 2500 years ago, well before the major increase in global population that has been hindcast from geometric models that assume a constant fractional rate of population increase. Some of this discrepancy has been reconciled by historical evidence showing much higher per-capita clearance millennia ago than later in pre-industrial time, resulting in disproportionately large early clearance and CO2 emissions. In addition, DNA studies and archeological syntheses now indicate that early farming populations initially grew at very fast rates favored by environments rich in basic resources (especially fertile soils), but then slowed in later millennia because of growing resource limitations and the effects of pandemics and civil strife in checking population growth. This emerging view of fast-rising early population trends has the potential to account for the early timing of the CO2 increase.

  17. A high sensitivity inductive sensor for blade tip clearance measurement

    NASA Astrophysics Data System (ADS)

    Du, Li; Zhu, Xiaoliang; Zhe, Jiang

    2014-06-01

    A multiplexed inductive sensor consisting of multiple mini-sized planar spiral coils for detecting multiple tip clearances of rotor blades is presented. The sensor measures the tip clearances by monitoring the inductance changes of planar spiral coils caused by the passage of the rotor blades. A resonance frequency division multiplexing technique and parallel LC resonance measurement were applied to the multiple sensor coils, making it feasible to measure multiple tip clearances using only one set of measurement electronics with high sensitivity and resolution. The results from tests conducted on a bench-top test rig have demonstrated that the sensor is capable of simultaneously measuring multiple tip clearances from 0 to 5 mm with a 10 μm resolution at a high rotary speed up to 80 000 RPM. With its high resolution, high sensitivity and capability of monitoring a large number of tip clearances simultaneously, this sensor can potentially be used for advanced active tip clearance control in turbine machinery.

  18. Calculation of Tip Clearance Effects in a Transonic Compressor Rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1998-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concern- ing the use of the simple clearance model Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computed results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  19. Calculation of tip clearance effects in a transonic compressor rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1996-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concerning the use of the simple clearance model. Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computer results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  20. Allometric scaling for predicting human clearance of bisphenol A.

    PubMed

    Collet, Séverine H; Picard-Hagen, Nicole; Lacroix, Marlène Z; Puel, Sylvie; Viguié, Catherine; Bousquet-Melou, Alain; Toutain, Pierre-Louis; Gayrard, Véronique

    2015-05-01

    The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man. PMID:25759244

  1. Urinary and metabolic clearances of arginine vasopressin in normal subjects

    SciTech Connect

    Moses, A.M.; Steciak, E.

    1986-08-01

    Synthetic arginine vasopressin (AVP) was infused into 11 hydrated normal subjects at five different infusion rates ranging from 10 to 350 U kg min . Each infusion rate was continued for 1 h, and urinary determinations were made on the 30- to 60-min specimens during which time there was no further rise in plasma AVP. Urinary AVP concentrations ( U/ml) and excretion rates ( U/min) increased linearly with increasing infusion rates, and the concentration of AVP in urine increased 120 times more rapid than plasma. Urinary and metabolic clearances of AVP also increased linearly with the maximum urinary clearance being 60.6% of the creatinine clearance. The total metabolic clearance of AVP (including urinary clearance) was 17.8 times that of the urinary clearance of AVP alone. These data clarify the relationships between plasma and urinary AVP in normal hydrated subjects during AVP infusion under steady-state conditions and emphasize the potential advantage of measuring urinary AVP as a monitor of endogenous AVP secretion. AVP was measured by radioimmunoassay.

  2. Model of mucociliary clearance in cystic fibrosis lungs.

    PubMed

    Kurbatova, P; Bessonov, N; Volpert, V; Tiddens, H A W M; Cornu, C; Nony, P; Caudri, D

    2015-05-01

    Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways. PMID:25746843

  3. Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice.

    PubMed

    Wang, He-Cheng; Zhang, Tao; Kuerban, Bolati; Jin, Ying-Lan; Le, Weidong; Hara, Hideo; Fan, Dong-Sheng; Wang, Yan-Jiang; Tabira, Takeshi; Chui, De-Hua

    2015-08-01

    The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targetingclearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention. PMID:26254061

  4. Astrocytes: Targets for Neuroprotection in Stroke

    PubMed Central

    Barreto, George; White, Robin E.; Ouyang, Yibing; Xu, Lijun; Giffard, Rona G.

    2011-01-01

    In the past two decades, over 1000 clinical trials have failed to demonstrate a benefit in treating stroke, with the exception of thrombolytics. Although many targets have been pursued, including antioxidants, calcium channel blockers, glutamate receptor blockers, and neurotrophic factors, often the focus has been on neuronal mechanisms of injury. Broader attention to loss and dysfunction of non-neuronal cell types is now required to increase the chance of success. Of the several glial cell types, this review will focus on astrocytes. Astrocytes are the most abundant cell type in the higher mammalian nervous system, and they play key roles in normal CNS physiology and in central nervous system injury and pathology. In the setting of ischemia astrocytes perform multiple functions, some beneficial and some potentially detrimental, making them excellent candidates as therapeutic targets to improve outcome following stroke and in other central nervous system injuries. The older neurocentric view of the central nervous system has changed radically with the growing understanding of the many essential functions of astrocytes. These include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and modulation of neuronal excitability. In this review, we will focus on those functions of astrocytes that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcome following cerebral ischemia. PMID:21521168

  5. 48 CFR 245.7001-4 - DD Form 1640, Request for Plant Clearance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Plant Clearance. 245.7001-4 Section 245.7001-4 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Plant Clearance Forms 245.7001-4 DD Form 1640, Request for Plant Clearance. Use to request plant clearance assistance...

  6. 48 CFR 245.7101-4 - DD Form 1640, Request for Plant Clearance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Plant Clearance. 245.7101-4 Section 245.7101-4 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Plant Clearance Forms 245.7101-4 DD Form 1640, Request for Plant Clearance. Use to request plant clearance assistance...

  7. A three-dimensional model of tracheobronchial particle distribution during mucociliary clearance in the human respiratory tract.

    PubMed

    Sturm, Robert

    2013-05-01

    Although theoretical approaches to tracheobronchial (TB) clearance have been continuously refined during the past decades, questions concerning the exact course of particle removal from the TB tree have been largely remained unsolved. In order to clarify this problem, three-dimensional patterns of mucociliary particle clearance have to be generated at pre-defined time points after particle exposure. Here, we present a mathematical method for the generation of respective clearance patterns. Three-dimensional transport paths of inhaled particles as well as spatial deposition patterns were generated by determining spatial information of all airway tubes passed by the particles and the particle deposition sites. Three-dimensional data were converted to a coordinate system, within which the trachea represented the z-axis. Visualization of stored data was realized with the help of a freely available program code that is specialized in processing huge data sets. Mucociliary clearance of deposited particular mass was computed by assuming (1) an interrelationship between mucus velocity and airway caliber and (2) an average tracheal mucus velocity of 5.5mm min(-1). Position of cleared particles within the spatial TB tree was determined at t=0 h (immediately after exposure), t=12 h and t=24 h. Spatial patterns of mucociliary clearance were computed for particles with a uniform geometric diameter of 5μm and a density of 1g cm(-3). Inhalation of the aerosol loaded with those particles took place under sitting breathing conditions (breathing frequency: 15min(-1), tidal volume: 750 ml). As demonstrated by the generated clearance patterns, mucociliary transport of 5μm particles is completed after 30 h. Within the first 12 h following aerosol exposure, about 75% of the initially deposited particular mass is removed from the TB tree. After 24 h, 95% of the particles have been cleared. Clearance patterns are characterized by a successive transition of maximal particle

  8. Galphaz negatively regulates insulin secretion and glucose clearance.

    PubMed

    Kimple, Michelle E; Joseph, Jamie W; Bailey, Candice L; Fueger, Patrick T; Hendry, Ian A; Newgard, Christopher B; Casey, Patrick J

    2008-02-22

    Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. (2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a Galphaz knock-out mouse model was utilized to determine whether Galphaz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between Galphaz-null and wild-type mice. There was also no difference between the insulin sensitivity of Galphaz-null mice and wild-type controls, as measured by insulin tolerance tests. Galphaz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in Galphaz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Galphaz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Galphaz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Galphaz-null islets in the absence of exogenous stimulation. These findings indicate that Galphaz may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes. PMID:18096703

  9. Succession planning.

    PubMed

    Catanzaro, Thomas E

    2006-03-01

    This article provides the reader with an appreciation of the diverse elements that go into a buy-sell, affiliation, or merger situation for veterinary practices. In the changing market place of American veterinary medicine, old paradigms no longer hold comfort. The generational differences are briefly explored herein as well as the new economic realities. A few examples are offered to illustrate just how much variability exists in the current business of veterinary medicine and the subsequent practice transitions needed to enhance value. Functioning models are explored, as well as affiliation and merger options. Practice valuation is discussed in general terms, referencing the cutting-edge factors. The six-point summary provides almost all practices a solid operational base for daily operations and succession planning. PMID:16442447

  10. Successful clearance of facial common warts by local hyperthermia: report of two cases.

    PubMed

    Ma, Yan; Huo, Wei; Hong, Yu-Xiao; Chen, Hong-Duo; Gao, Xing-Hua

    2012-01-01

    Facial common wart is a disfiguring condition caused by human papilloma virus infection. Choices to treat facial warts should be cautious, in consideration of adverse cosmetic consequences. Two cases of facial common warts were treated by local hyperthermia at 44 °C for 30 minutes, once a day for three consecutive days (the first session), and similarly treated a week later for more 2 days (second session). The warts completely disappeared in 10 and 12 weeks, respectively in the two patients. Adverse effect was tolerable burning sensation in the two patients and a temporary heat-induced blistering in one of them. This pioneer trial suggested that mild hyperthermia is a safe and effective method in treating facial common warts. PMID:22950567

  11. High Power Cryogenic Targets

    SciTech Connect

    Gregory Smith

    2011-08-01

    The development of high power cryogenic targets for use in parity violating electron scattering has been a crucial ingredient in the success of those experiments. As we chase the precision frontier, the demands and requirements for these targets have grown accordingly. We discuss the state of the art, and describe recent developments and strategies in the design of the next generation of these targets.

  12. Clearance mechanism assignment and total clearance prediction in human based upon in silico models.

    PubMed

    Lombardo, Franco; Obach, R Scott; Varma, Manthena V; Stringer, Rowan; Berellini, Giuliano

    2014-05-22

    We introduce a two-tier model based on an exhaustive data set, where discriminant models based on principal component analysis (PCA) and partial least squares (PLS) are used separately and in conjunction, and we show that PCA is highly discriminant approaching 95% accuracy in the assignment of the primary clearance mechanism. Furthermore, the PLS model achieved a quantitative predictive performance comparable to methods based on scaling of animal data while not requiring the use of either in vivo or in vitro data, thus sparing the use of animal. This is likely the highest performance that can be expected from a computational approach, and further improvements may be difficult to reach. We further offer the medicinal scientist a PCA model to guide in vitro and/or in vivo studies to help limit the use of resources via very rapid computations. PMID:24773013

  13. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease.

    PubMed

    Baranello, Robert J; Bharani, Krishna L; Padmaraju, Vasudevaraju; Chopra, Nipun; Lahiri, Debomoy K; Greig, Nigel H; Pappolla, Miguel A; Sambamurti, Kumar

    2015-01-01

    Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for A

  14. Successful Lecturing

    PubMed Central

    Copeland, H Liesel; Longworth, David L; Hewson, Mariana G; Stoller, James K

    2000-01-01

    OBJECTIVE In a study conducted over 3 large symposia on intensive review of internal medicine, we previously assessed the features that were most important to course participants in evaluating the quality of a lecture. In this study, we attempt to validate these observations by assessing prospectively the extent to which ratings of specific lecture features would predict the overall evaluation of lectures. MEASUREMENTS AND MAIN RESULTS After each lecture, 143 to 355 course participants rated the overall lecture quality of 69 speakers involved in a large symposium on intensive review of internal medicine. In addition, 7 selected participants and the course directors rated specific lecture features and overall quality for each speaker. The relations among the variables were assessed through Pearson correlation coefficients and cluster analysis. Regression analysis was performed to determine which features would predict the overall lecture quality ratings. The features that most highly correlated with ratings of overall lecture quality were the speaker's abilities to identify key points (r = .797) and be engaging (r = .782), the lecture clarity (r = .754), and the slide comprehensibility (r = .691) and format (r = .660). The three lecture features of engaging the audience, lecture clarity, and using a case-based format were identified through regression as the strongest predictors of overall lecture quality ratings (R2= 0.67, P = 0.0001). CONCLUSIONS We have identified core lecture features that positively affect the success of the lecture. We believe our findings are useful for lecturers wanting to improve their effectiveness and for educators who design continuing medical education curricula. PMID:10886470

  15. Pulmonary function and clearance after prolonged sulfuric acid aerosol exposure

    SciTech Connect

    Ives, P.J. ); Gerrity, T.R.; DeWitt, P.; Folinsbee, L.J. )

    1991-03-15

    The authors studied pulmonary function and clearance responses after a 4 H exposure to 75-100 {mu}g/m{sup 3} sulfuric acid aerosol (SAA). Healthy subjects, who exercised for 30 min/H at ventilation of about 25 L/min, were exposed once to clean air and once to SAA. Oral hygiene and acidic juice gargle were used to minimize oral ammonia. Lung function tests, including spirometry, plethysmography, and partial flow-volume (PEFV) curves were performed before and after exposure. Clearance of 99m-Technetium labeled iron oxide was assessed after each exposure. The first moment of fractional tracheobronchial retention (M1TBR), after correcting for 24 H retention and normalizing to time zero, was used as an index of clearance. There were no significant changes in lung volumes, airways resistance, or maximum expiratory flows after SAA exposure. Flow at 40% of total lung capacity on PEFV curves decreased 17% (NS) after SAA exposure. Tracheobronchial clearance was accelerated after a single exposure to SAA; M1TBR decreased from 73 {plus minus} 5 min (air) to 69 {plus minus} 5 min (SAA). These results suggest that acute prolonged exposure to low levels of SAA has minimal effects on lung mechanics in healthy subjects but does produce a modest acceleration of particle clearance.

  16. Experimental and Numerical Study on Blanking Process with Negative Clearance

    NASA Astrophysics Data System (ADS)

    Hirota, Kenji; Yanaga, Hiroki; Fukushima, Katsunori

    This study summarizes the characteristics of blanking behavior with a negative clearance. Several experiments were performed for two aluminum sheets over a wide range of clearances including negative values. Blanking with negatively large clearances was found to produce fine cut edges with less roll-over and no fracture zone even for a brittle material. Corresponding simulations were performed using the Ayada's criterion for predicting ductile fracture initiation. Each zone of blanked part edges such as roll-over and fractured zone agreed well with that obtained in the experiments except a few cases accompanied by secondary shear. The reason for prevention of fracture by using negative clearances was explained with the change of the damage value during the process; the damage value was kept low throughout the blanking operation since the mean stress dominating the damage value became compressive around the die edge. Influences of blanking parameters on load-stroke curves were also investigated. The curves for negative clearances showed gradual increase in load toward the end of stroke. The earlier fracture initiated, the earlier the load reached a peak. Simulated curves showed the same tendency and in good agreement with the experimental ones quantitatively.

  17. ELMO1 signaling in apoptotic germ cell clearance and spermatogenesis.

    PubMed

    Elliott, Michael R; Ravichandran, Kodi S

    2010-10-01

    Apoptosis and the subsequent removal of dying cells are crucial processes for tissue development and maintenance. Although we are beginning to understand the signaling pathways that control the phagocytic clearance of apoptotic cells, the physiological relevance of these pathways is lacking. During spermatogenesis, over half of the developing germ cells eventually die by apoptosis, yet the signaling pathways that regulate the phagocytic clearance of these dying cells or the impact of this clearance on development and maintenance of the germ cell population is not well understood. The ELMO1/Dock180 proteins form an evolutionarily conserved signaling module that functions as a bipartite guanine nucleotide exchange factor for the small GTPase Rac. The subsequent Rac-dependent cytoskeletal changes play an important role in the physical engulfment of apoptotic cells. Recent findings demonstrate an in vivo role for ELMO1-dependent clearance in the testes, with implications for spermatogenesis. Here we will discuss the role of apoptotic cell clearance during spermatogenesis, with a particular emphasis on ELMO1/Dock180 signaling. PMID:20958313

  18. Renal Clearance and Degradation of Glutathione-Coated Copper Nanoparticles

    PubMed Central

    Yang, Shengyang; Sun, Shasha; Zhou, Chen; Hao, Guiyang; Liu, Jinbin; Ramezani, Saleh; Yu, Mengxiao; Sun, Xiankai; Zheng, Jie

    2016-01-01

    Degradation of inorganic nanoparticles (NPs) into small molecular complexes is often observed in the physiological environment; however, how this process influences renal clearance of inorganic NPs is largely unknown. By systematically comparing renal clearance of degradable luminescent glutathione coated copper NPs (GS-CuNPs) and their dissociated products, Cu(II)-glutathione disulfide (GSSG) complexes (Cu(II)-GSSG), we found that GS-CuNPs were eliminated through the urinary system surprisingly faster and accumulated in the liver much less than their smaller dissociation counterparts. With assistance of radiochemistry and positron emission tomography (PET) imaging, we found that the observed “nano size” effect in enhancing renal clearance is attributed to the fact that GS-CuNPs are more resistant to serum protein adsorption than Cu(II)-GSSG. In addition, since dissociation of GS-CuNPs follows zero-order chemical kinetics, their renal clearance and biodistribution also depend on initial injection doses and their dissociation processes. Quantitative understanding of size effect and other factors involved in renal clearance and biodistribution of degradable inorganic NPs will lay down a foundation for further development of renal-clearable inorganic NPs with minimized nanotoxicity. PMID:25674666

  19. An evaluation of hepatic extraction and clearance of doxorubicin.

    PubMed Central

    August, D. A.; Verma, N.; Vaertan, M. A.; Shah, R.; Brenner, D. E.

    1995-01-01

    A swine model was developed to study quantitatively the pharmacokinetics of hepatic extraction and clearance of doxorubicin (DOX). Systemic and hepatic artery infusions of DOX (0.5-9 mg kg-1) were administered to 34 pigs. Pharmacokinetic analysis was simplified by use of a double-balloon catheter in the inferior vena cava to collect hepatic venous effluent. During hepatic artery infusion only, DOX in hepatic venous blood was extracted using activated carbon filters to prevent drug recirculation. Hepatic extraction and clearance of DOX were independent of dose and route of administration. Extraction ratios varied from 0.75 to 0.91 during hepatic artery infusion and from 0.50 to 0.72 during systemic infusion. Clearance results were analogous. After cessation of drug infusions, hepatic extraction and clearance of DOX was negative, suggesting that the liver serves as a drug reservoir during DOX infusion and subsequently is a net source of unmetabolised drug. Liver extraction and clearance of DOX in pigs are substantial. During either systemic or hepatic artery infusion of DOX, the liver serves as a drug reservoir. Subsequent mobilisation of this hepatic pool of DOX may cause prolonged systemic exposure to drug. PMID:7599068

  20. Periodic response of multi-disk rotors with bearing clearances

    NASA Technical Reports Server (NTRS)

    Kim, Y. B.; Noah, S. T.; Choi, Y. S.

    1991-01-01

    The forced steady state response of a multi-disk rotor system involving a clearance at one of the bearings is determined by using a harmonic balance approach. The impedance method is applied to each of the harmonic steady state components in order to reduce the system to its displacement at the nonlinear bearing support. The results reveal the interrelated roles of the bearing clearance, mass eccentricity and side force in producing dangerous subharmonics. The significant effects of the strong nonlinearity of a bearing clearance are studied as related to the various system parameters. The results show that the approach developed in this study is computationally superior to numerical integration methods in analyzing multi-disk rotor systems with strong nonlinearity.

  1. Periodic response of multi-disk rotors with bearing clearances

    NASA Astrophysics Data System (ADS)

    Kim, Y. B.; Noah, S. T.; Choi, Y. S.

    1991-02-01

    The forced steady state response of a multi-disk rotor system involving a clearance at one of the bearings is determined by using a harmonic balance approach. The impedance method is applied to each of the harmonic steady state components in order to reduce the system to its displacement at the non-linear bearing support. The results reveal the interrelated roles of the bearing clearance, mass eccentricity and side force in producing dangerous subharmonics. The significant effects of the strong non-linearity of a bearing clearance are studied as related to the various system parameters. The results show that the approach developed in this study is computationally superior to numerical integration methods in analyzing multi-disk rotor systems with strong non-linearity.

  2. HPT Clearance Control: Intelligent Engine Systems-Phase 1

    NASA Technical Reports Server (NTRS)

    2005-01-01

    The following work has been completed to satisfy the Phase I Deliverables for the "HPT Clearance Control" project under NASA GRC's "Intelligent Engine Systems" program: (1) Need for the development of an advanced HPT ACC system has been very clearly laid out, (2) Several existing and potential clearance control systems have been reviewed, (3) A scorecard has been developed to document the system, performance (fuel burn, range, payload, etc.), thermal, and mechanical characteristics of the existing clearance control systems, (4) Engine size and flight cycle selection for the advanced HPT ACC system has been reviewed with "large engine"/"long range mission" combination showing the most benefit, (5) A scoring criteria has been developed to tie together performance parameters for an objective, data driven comparison of competing systems, and (6) The existing HPT ACC systems have been scored based on this scoring system.

  3. Bromosulphophthalein clearance rates in sheep with pyrrolizidine liver damage.

    PubMed

    Lanigan, G W; Peterson, J E

    1979-05-01

    Sheep fed a ration containing 50% of dried Heliotropium europaeum showed a marked decline in bromosulphophthalein (BSP) fractional clearance rate during the first 3 months feeding. Thereafter, the response of individual animals varied widely on a time basis, although 3 groups could be identified. In the terminal stages, mean clearance rates were below 20% of initial values, with some sheep showing a decline in excess of 90%. Loss of liver functional capacity was generally much greater than indicated by the degree of damage revealed by histopathology. Thus, a suitably modified test could have considerable prognostic value in the field. In this investigation, all sheep with clearance rates below 0.15 died when exposed to a further period of H. europaeum feeding. PMID:475677

  4. Inefficient clearance of myelin debris by microglia impairs remyelinating processes

    PubMed Central

    Lampron, Antoine; Larochelle, Antoine; Laflamme, Nathalie; Préfontaine, Paul; Plante, Marie-Michèle; Sánchez, Maria Gabriela; Yong, V. Wee; Stys, Peter K.; Tremblay, Marie-Ève

    2015-01-01

    An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow–derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired. PMID:25779633

  5. Application of Dsm in Obstacle Clearance Surveying of Aerodrome

    NASA Astrophysics Data System (ADS)

    Qiao, X.; Lv, S. H.; Li, L. L.; Zhou, X. J.; Wang, H. Y.; Li, D.; Liu, J. Y.

    2016-06-01

    Compared to the wide use of digital elevation model (DEM), digital surface model (DSM) receives less attention because that it is composed by not only terrain surface, but also vegetations and man-made objects which are usually regarded as useless information. Nevertheless, these objects are useful for the identification of obstacles around an aerodrome. The primary objective of the study was to determine the applicability of DSM in obstacle clearance surveying of aerodrome. According to the requirements of obstacle clearance surveying at QT airport, aerial and satellite imagery were used to generate DSM, by means of photogrammetry, which was spatially analyzed with the hypothetical 3D obstacle limitation surfaces (OLS) to identify the potential obstacles. Field surveying was then carried out to retrieve the accurate horizontal position and height of the obstacles. The results proved that the application of DSM could make considerable improvement in the efficiency of obstacle clearance surveying of aerodrome.

  6. Fiber-optic laser Doppler turbine tip clearance probe

    NASA Astrophysics Data System (ADS)

    Büttner, Lars; Pfister, Thorsten; Czarske, Jürgen

    2006-05-01

    A laser Doppler based method for in situ single blade tip clearance measurements of turbomachines with high precision is presented for what we believe is the first time. The sensor is based on two superposed fanlike interference fringe systems generated by two laser wavelengths from a fiber-coupled, passive, and therefore compact measurement head employing diffractive optics. Tip clearance measurements at a transonic centrifugal compressor performed during operation at 50,000 rpm (833 Hz, 586 m/s tip speed) are reported. At these speeds the measured uncertainty of the tip position was less than 20 μm, a factor of 2 more accurate than that of capacitive probes. The sensor offers great potential for in situ and online high-precision tip clearance measurements of metallic and nonmetallic turbine blades.

  7. Fiber-optic laser Doppler turbine tip clearance probe.

    PubMed

    Büttner, Lars; Pfister, Thorsten; Czarske, Jürgen

    2006-05-01

    A laser Doppler based method for in situ single blade tip clearance measurements of turbomachines with high precision is presented for what we believe is the first time. The sensor is based on two superposed fanlike interference fringe systems generated by two laser wavelengths from a fiber-coupled, passive, and therefore compact measurement head employing diffractive optics. Tip clearance measurements at a transonic centrifugal compressor performed during operation at 50,000 rpm (833 Hz, 586 m/s tip speed) are reported. At these speeds the measured uncertainty of the tip position was less than 20 microm, a factor of 2 more accurate than that of capacitive probes. The sensor offers great potential for in situ and online high-precision tip clearance measurements of metallic and nonmetallic turbine blades. PMID:16642064

  8. Impaired lipid clearance in patients with previous acute pancreatitis.

    PubMed Central

    Guzmán, S; Nervi, F; Llanos, O; León, P; Valdivieso, V

    1985-01-01

    Fasting serum triglycerides were measured in 52 patients who had sustained an attack of pancreatitis (gall stone related 33, alcoholism six) at least six months earlier. Several patients (23%) had raised fasting serum triglycerides, with a type IV phenotype in all but one patient. The 40 patients with normal fasting serum triglycerides received an oral load of 100 g sunflower oil to compare their clearance of dietary triglycerides with that of a control group of 54 subjects. The clearance of ingested triglycerides was significantly impaired in the patients - irrespective of the presumed aetiological factor, or clinical condition associated with pancreatitis - compared with the clearance in controls. A triglyceride tolerance test is the only way to detect those patients in whom a future attack of pancreatitis may be precipitated by a diet rich in fat, or endogenous over production of triglycerides as after an alcoholic debauch. PMID:4029716

  9. Effect of Internal Clearance on Load Distribution and Life of Radially Loaded Ball and Roller Bearings

    NASA Technical Reports Server (NTRS)

    Oswald, Fred B.; Zaretsky, Erwin V.; Poplawski, Joseph V.

    2012-01-01

    The effect of internal clearance on radially loaded deepgroove ball and cylindrical roller bearing load distribution and fatigue life was determined for four clearance groups defined in the bearing standards. The analysis was extended to negative clearance (interference) conditions to produce a curve of life factor versus internal clearance. Rolling-element loads can be optimized and bearing life maximized for a small negative operating clearance. Life declines gradually with positive clearance and rapidly with increasing negative clearance. Relationships were found between bearing life and internal clearance as a function of ball or roller diameter, adjusted for load. Results are presented as life factors for radially loaded bearings independent of bearing size or applied load. In addition, a modified Stribeck Equation is presented that relates the maximum rolling-element load to internal bearing clearance.

  10. Clearance of Staphylococcus aureus nasal carriage is T cell dependent and mediated through interleukin-17A expression and neutrophil influx.

    PubMed

    Archer, Nathan K; Harro, Janette M; Shirtliff, Mark E

    2013-06-01

    The anterior nares of humans are the major reservoir for Staphylococcus aureus colonization. Approximately 20% of the healthy human population is persistently and 80% is intermittently colonized with S. aureus in the nasal cavity. Previous studies have shown a strong causal connection between S. aureus nasal carriage and increased risk of nosocomial infection, as well as increased carriage due to immune dysfunction. However, the immune responses that permit persistence or mediate clearance of S. aureus on the nasal mucosa are fundamentally undefined. In this study, we developed a carriage model in C57BL/6J mice and showed that clearance begins 14 days postinoculation. In contrast, SCID mice that have a deficient adaptive immune response are unable to eliminate S. aureus even after 28 days postinoculation. Furthermore, decolonization was found to be T cell mediated but B cell independent by evaluating carriage clearance in T-cell receptor β/δ (TCR-β/δ) knockout (KO) and IgH-μ KO mice, respectively. Upregulation of the cytokines interleukin 1β (IL-1β), KC (also termed CXC ligand 1 [CXCL1]), and IL-17A occurred following inoculation with intranasal S. aureus. IL-17A production was crucial for clearance, since IL-17A-deficient mice were unable to effectively eliminate S. aureus carriage. Subsequently, cell differential counts were evaluated from nasal lavage fluid obtained from wild-type and IL-17A-deficient colonized mice. These counts displayed IL-17A-dependent neutrophil migration. Antibody-mediated depletion of neutrophils in colonized mice caused reduced clearance compared to that in isotype-treated controls. Our data suggest that the Th17-associated immune response is required for nasal decolonization. This response is T cell dependent and mediated via IL-17A production and neutrophil influx. Th17-associated immune responses may be targeted for strategies to mitigate distal infections originating from persistent S. aureus carriage in humans. PMID:23529621

  11. The Therapeutic Role of Vasopressin on Improving Lactate Clearance During and After Vasogenic Shock: Microcirculation, Is It The Black Box?

    PubMed

    Barzegar, Elchin; Ahmadi, Arezoo; Mousavi, Sarah; Nouri, Masoumeh; Mojtahedzadeh, Mojtaba

    2016-01-01

    Arginine vasopressin as a supplementary vasopressor in septic shock restores vascular tone and mean arterial pressure, meanwhile decreases dose and exposure time to catecholamines. The objective of this study was to evaluate the effect of vasopressin on lactate and lactate clearance as markers of tissue perfusion during septic shock. In this prospective, randomized, controlled trial, 30 patients with septic shock were enrolled in two groups. One group received norepinephrine infusion (titrated to reach the target MAP of ≥65 mm Hg) and the other group in addition to norepinephrine, received vasopressin at a constant rate of 0.03 u/min. Serum lactate levels were assessed at baseline, 24 and 48 hours after randomization. Lactate clearance was estimated for each patient at 24 and 48 hours. Venous lactate was measured in both groups. Despite a tendency toward higher venous lactate at 24 and 48 hours in the norepinephrine group (3.1 vs. 2.5, P=0.67 and 1.7 vs. 1.1, P=0.47), the conflict was not statistically significant among them. While lactate clearance after 24 hours was significantly higher in vasopressin treatment group (46% vs. 20%, respectively; P=0.048), the 48-hour lactate clearance did not differ from statistic viewpoints despite their clinical values (66% vs. 40%, P=0.17). Although lactate levels did not significantly differ between treatment groups, lactate clearance at 24 hours was significantly higher in vasopressin group. This may be the effect of vasopressin effect on microcirculation and tissue hypoperfusion or its catecholamine sparing effect. PMID:26853286

  12. Successful Predictions

    NASA Astrophysics Data System (ADS)

    Pierrehumbert, R.

    2012-12-01

    In an observational science, it is not possible to test hypotheses through controlled laboratory experiments. One can test parts of the system in the lab (as is done routinely with infrared spectroscopy of greenhouse gases), but the collective behavior cannot be tested experimentally because a star or planet cannot be brought into the lab; it must, instead, itself be the lab. In the case of anthropogenic global warming, this is all too literally true, and the experiment would be quite exciting if it weren't for the unsettling fact that we and all our descendents for the forseeable future will have to continue making our home in the lab. There are nonetheless many routes though which the validity of a theory of the collective behavior can be determined. A convincing explanation must not be a"just-so" story, but must make additional predictions that can be verified against observations that were not originally used in formulating the theory. The field of Earth and planetary climate has racked up an impressive number of such predictions. I will also admit as "predictions" statements about things that happened in the past, provided that observations or proxies pinning down the past climate state were not available at the time the prediction was made. The basic prediction that burning of fossil fuels would lead to an increase of atmospheric CO2, and that this would in turn alter the Earth's energy balance so as to cause tropospheric warming, is one of the great successes of climate science. It began in the lineage of Fourier, Tyndall and Arrhenius, and was largely complete with the the radiative-convective modeling work of Manabe in the 1960's -- all well before the expected warming had progressed far enough to be observable. Similarly, long before the increase in atmospheric CO2 could be detected, Bolin formulated a carbon cycle model and used it to predict atmospheric CO2 out to the year 2000; the actual values come in at the high end of his predicted range, for

  13. Population success.

    PubMed

    1982-01-01

    "The commitment to population programs is now widespread," says Rafael Salas, Executive Director of the UNFPA, in its report "State of World Population." About 80% of the total population of the developing world live in countries which consider their fertility levels too high and would like them reduced. An important impetus came from the World Conference of 1974. The Plan of Action from the conference projected population growth rates in developing countries of 2.0% by 1985. Today it looks as though this projection will be realized. While in 1969, for example, only 26 developing countries had programs aimed at lowering or maintaining fertility levels, by 1980 there were 59. The International Population Conference, recently announced by the UN for 1984, will, it is hoped, help sustain that momentum. Cuba is the country which has shown the greatest decline in birth rate so far. The birth rate fell 47% between 1965-1970 and 1975-1980. Next came China with a 34% decline in the same period. After these came a group of countries--each with populations of over 10 million--with declines of between 15 and 25%: Chile, Colombia, India, Indonesia, the Republic of Korea, Malaysia and Thailand. Though birth rates have been dropping significantly the decline in mortality rates over recent years has been less than was hoped for. The 1974 conference set 74 years as the target for the world's average expectation of life, to be reached by the year 2000. But the UN now predicts that the developing countries will have only reached 63 or 64 years by then. High infant and child mortality rates, particularly in Africa, are among the major causes. The report identifies the status of women as an important determinant of family size. Evidence from the UNFPA-sponsored World Fertility Survey shows that in general the fertility of women decreases as their income increases. It also indicates that women who have been educated and who work outside the home are likely to have smaller families

  14. Acute exposure to acid fog. Effects on mucociliary clearance

    SciTech Connect

    Laube, B.L.; Bowes, S.M. III; Links, J.M.; Thomas, K.K.; Frank, R. )

    1993-05-01

    Submicrometric sulfuric acid (H2SO4) aerosol can affect mucociliary clearance without eliciting irritative symptoms or changes in pulmonary function. The effect of larger fog droplets containing H2SO4 on mucociliary clearance is unknown. We quantified mucociliary clearance from the trachea (n = 4) and small airways (n = 7) of young healthy male adults after an acute exposure to H2SO4 fog (MMAD = 10.3 microns; pH = 2.0; liquid water content = 481 +/- 65 mg/m3; osmolarity = 30 mOsm). Acid fog (AF) or saline fog (SF) (10.9 microns; 492 +/- 116 mg/m3; 30 mOsm) was administered for 40 min of unencumbered breathing (no mouth-piece) at rest and for 20 min of exercise sufficient to produce oronasal breathing. Fog exposures were followed by a methacholine (MCh) challenge (a measure of airway reactivity) or inhalation of technetium-99M radioaerosol (MMAD = 3.4 microns) on 2 study days each. Changes in symptoms and forced ventilatory function were also assessed. Clearance was quantified from computer-assisted analyses of gamma camera images of the lower respiratory tract in terms of %removal/min of the radiolabel from the trachea 25 min after inhalation and from the outer zone of the right lung after 1.9 to 3 h. Symptoms, forced ventilatory function, and MCh response were unaffected by either fog. Tracheal clearance was more rapid in four of four subjects after AF (0.83 +/- 1.58% removal/min) compared with that after SF (-0.54 +/- 0.85% removal/min). Outer zone clearance was more rapid in six of seven subjects after AF (0.22 +/- 0.15% removal/min) compared with that after SF (0.01 +/- 0.09% removal/min).

  15. Modulation of lung liquid clearance by isoproterenol in rat lungs.

    PubMed

    Saldías, F; Lecuona, E; Friedman, E; Barnard, M L; Ridge, K M; Sznajder, J I

    1998-05-01

    beta-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which beta-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10(-4) to 10(-8) M increased lung liquid clearance compared with that of control lungs (P < 0.01). The increase in lung liquid clearance was inhibited by the beta-antagonist propranolol (10(-5) M), the Na(+)-channel blocker amiloride (10(-4) M), and the antagonist of Na-K-ATPase, ouabain (5 x 10(-4) M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase alpha 1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10(-6) M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase alpha 1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of beta-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+ pumps to the plasma membrane participate in beta-adrenergic stimulation of lung liquid clearance in rat lungs. PMID:9612284

  16. Effects of desipramine on norepinephrine clearance in congestive heart failure

    SciTech Connect

    Clemson, B.; Baily, R.G.; Davis, D.; Zelis, R. )

    1990-08-01

    Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of (3H)NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

  17. Mucociliary clearance, airway inflammation and nasal symptoms in urban motorcyclists

    PubMed Central

    Brant, Tereza C S; Yoshida, Carolina T; de S. Carvalho, Tomas; Nicola, Marina L; Martins, Jocimar A; Braga, Lays M; de Oliveira, Regiani C; Leyton, Vilma; de André, Carmen S; Saldiva, Paulo H N; Rubin, Bruce K; Nakagawa, Naomi K

    2014-01-01

    OBJECTIVES: There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution. METHODS: In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO2) concentration-monitoring system during the 14 days before each assessment. The associations between NO2 and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: NCT01976039. RESULTS: Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO2 exposure level was 75 mg/m3 for these subjects and a significant association was observed between NO2 and impaired mucociliary clearance (p = 0.036). CONCLUSION: Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution. PMID:25628001

  18. Neuronal aggregates: formation, clearance and spreading

    PubMed Central

    Lim, Junghyun; Yue, Zhenyu

    2015-01-01

    Summary Proteostasis is maintained by multiple cellular pathways, including protein synthesis, quality control and degradation. An imbalance of neuronal proteostasis, associated with protein misfolding and aggregation, leads to proteinopathies or neurodegeneration. While genetic variations and protein modifications contribute to aggregate formation, components of the proteostasis network dictate the fate of protein aggregates. Here we provide an overview of proteostasis pathways and their interplay (particularly autophagy) with the metabolism of disease-related proteins. We review recent studies on neuronal activity-mediated regulation of proteostasis and transcellular propagation of protein aggregates in the nervous system. Targeting proteostasis pathways therapeutically remains an attractive but challenging task. PMID:25710535

  19. Hepatitis C Virus Infection and Its Clearance Alter Circulating Lipids: Implications for Long Term Follow-up

    PubMed Central

    Corey, Kathleen E; Kane, Erin; Munroe, Craig; Barlow, Lydia L.; Zheng, Hui; Chung, Raymond T

    2015-01-01

    Hepatitis C associated hypolipidemia has been demonstrated in studies from Europe and Africa. In 2 linked studies we evaluated the relationship between hepatitis C infection and treatment with lipid levels in an American cohort and determined the frequency of clinically significant post-treatment hyperlipidemia. A case-control analysis of patients with and without hepatitis C was performed. The Hepatitis C Group consisted of 179 infected patients. The Uninfected Control Group consisted of 180 age matched controls. Fasting cholesterol, low density lipoprotein (LDL), high density lipoprotein and triglycerides were compared. The second group was a retrospective cohort (Treated Hepatitis C Group) of 87 treated Hepatitis C patients with lipid data before and after therapy. In the case-control analysis, the Hepatitis C Group had significantly lower LDL and cholesterol than the Uninfected Control Group. In the retrospective cohort, patients in the Treated Hepatitis C Group who achieved viral clearance had increased LDL and cholesterol from baseline compared to patients without viral clearance. These results persisted when adjusted for age, sex and genotype. 13% of patients with viral clearance had increased LDL and 33% experienced increases in cholesterol to levels warranting lipid lowering therapy. Conclusion Hepatitis C is associated with decreased cholesterol and LDL levels. This hypolipidemia resolves with successful hepatitis C treatment but persists in non-responders. A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk. Lipids should be carefully monitored in persons receiving antiviral therapy. PMID:19787818

  20. Clearance Analysis of CTC2 (on ELC4) to S-TRRJ HRS Radiator Rotation Envelope

    NASA Technical Reports Server (NTRS)

    Liddle, Donn

    2014-01-01

    ) as defined by nine preexisting Space Vision System (SVS) targets affixed to the forward/zenith side of the S1 and S3 truss segments. The location of the outboard edge of the S-TRRJ radiator would also be measured when positioned at the angle of closest approach to CTC2 (gamma = 35.0 degrees). This data would allow the Digital Pre-Assembly Group to predict how the ELC4 would sit on the UCCAS and how that would translate into the clearance between CTC2 and the S-TRRJ radiators. Phase II: After the ELC4 was delivered and installed into the UCCAS, the position of the CTC2 mounting plate on the inboard face of ELC4, would be measured in the ISSACS coordinate system relative to the SVS control points used in Phase I. Although CTC2 would not yet be mounted on ELC4, the working envelope of CTC2 could be mathematically added to the measured position of ELC4 to produce a best estimate for CTC2's mounted location. Comparing CTC2's best estimated location to the S-TRRJ radiator (measured in Phase I); relative to the ISSACS coordinate system, would provide a direct measurement of the expected clearance. Due to the impending delivery of ELC4 (scheduled for January 2011), planning for the Phase I clearance analysis began immediately. Using the Dynamic Onboard Ubiquitous Graphics (DOUG) program, ISAG designed a way to acquire images of the SVS control points on truss segments S1 and S3, the aft facing edge of the S-TRRJ Heat Rejection Subsystem (HRS) radiator, and the three UCCAS latch mechanisms mounted on the zenith face of the S3 truss using the Space Station Remote Manipulator System (SSRMS). To minimize the number of SSRMS movements, the Special Purpose Dexterous Manipulator (SPDM) would be attached to the SSRMS. This would make it possible to park the SPDM in one position and acquire multiple images by changing the viewing orientation of the SPDM body cameras using the pan/tilt units on which they are mounted. Using this implementation concept, ISAG identified four SSRMS

  1. Effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody.

    PubMed

    Kasai, Noriyuki; Yoshikawa, Yukitaka; Enokizono, Junichi

    2014-01-01

    Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KM3566 is a mouse anti-HB-EGF monoclonal antibody that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. Based on the results of our pharmacokinetics study, a humanized derivative antibody, KHK2866, is rapidly cleared from serum and shows nonlinear pharmacokinetics in cynomolgus monkeys. In this study, we examined the antigen-dependent clearance of an anti-HB-EGF monoclonal antibody in vivo and in vitro in order to pharmacokinetically explain the rapid elimination of KHK2866. We revealed tumor size-dependent clearance of KM3566 in in vivo studies and obtained good fits between the observed and simulated concentrations of KM3566 based on the two-compartment with a saturable route of clearance model. Furthermore, in vivo imaging analyses demonstrated tumor-specific distribution of KM3566. We then confirmed rapid internalization and distribution to lysosome of KM3566 at a cellular level. Moreover, we revealed that the amounts of HB-EGF on cell surface membrane were maintained even while HB-EGF was internalized with KM3566. Recycled or newly synthesized HB-EGF, therefore, may contribute to a consecutive clearance of KM3566, which could explain a rapid clearance from serum. These data suggested that the rapid elimination in pharmacokinetics of KM3566 is due to antigen-dependent clearance. Given that its antigen is expressed in a wide range of normal tissue, it is estimated that the rapid elimination of KHK2866 from cynomolgus monkey serum is caused by antigen-dependent clearance. PMID:25517307

  2. Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model.

    PubMed

    Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R; Avram, Michael J; Coppeta, Jonathan R; Wishnok, John S; Borenstein, Jeffrey T; Tannenbaum, Steven R

    2016-02-01

    The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior. PMID:26586376

  3. Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

    PubMed Central

    Guo, Dongwei; Zhang, Gang; Wysocki, Tadeusz A.; Wysocki, Beata J.; Gelbard, Harris A.; Liu, Xin-Ming; McMillan, JoEllyn M.

    2014-01-01

    ABSTRACT Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ∼1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nanoATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance. IMPORTANCE The need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART

  4. The E3-Ubiquitin Ligase TRIM50 Interacts with HDAC6 and p62, and Promotes the Sequestration and Clearance of Ubiquitinated Proteins into the Aggresome

    PubMed Central

    Fusco, Carmela; Micale, Lucia; Egorov, Mikhail; Monti, Maria; D’Addetta, Ester Valentina; Augello, Bartolomeo; Cozzolino, Flora; Calcagnì, Alessia; Fontana, Andrea; Polishchuk, Roman S.; Didelot, Gerard; Reymond, Alexandre; Pucci, Piero; Merla, Giuseppe

    2012-01-01

    In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance. PMID:22792322

  5. Higher-dimensional targeting

    SciTech Connect

    Kostelich, E.J. ); Grebogi, C. Department of Mathematics and Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20742 ); Ott, E. Department of Electrical Engineering, University of Maryland, College Park, Maryland 20742 ); Yorke, J.A. )

    1993-01-01

    This paper describes a procedure to steer rapidly successive iterates of an initial condition on a chaotic attractor to a small target region about any prespecified point on the attractor using only small controlling perturbations. Such a procedure is called targeting.'' Previous work on targeting for chaotic attractors has been in the context of one- and two-dimensional maps. Here it is shown that targeting can also be done in higher-dimensional cases. The method is demonstrated with a mechanical system described by a four-dimensional mapping whose attractor has two positive Lyapunov exponents and a Lyapunov dimension of 2.8. The target is reached by making very small successive changes in a single control parameter. In one typical case, 35 iterates on average are required to reach a target region of diameter 10[sup [minus]4], as compared to roughly 10[sup 11] iterates without the use of the targeting procedure.

  6. Low-density lipoprotein receptor-related protein-1 : a serial clearance homeostatic mechanism controlling Alzheimer's amyloid β-peptide elimination from the brain

    PubMed Central

    Zlokovic, Berislav V.; Deane, Rashid; Sagare, Abhay P.; Bell, Robert D.; Winkler, Ethan A.

    2010-01-01

    Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the LDL receptor family, has major roles in the cellular transport of cholesterol, endocytosis of forty structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid β-peptide (Aβ). According to the two hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Aβ accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a three-level serial LRP1-dependent homeostatic control of Aβ clearance including (i) cell-surface LRP1 at the BBB and cerebrovascular cells mediating brain-to-blood Aβ clearance (ii) circulating LRP1 providing a key endogenous peripheral ‘sink’ activity for plasma Aβ which prevents free Aβ access to the brain, and (iii) LRP1 in the liver mediating systemic Aβ clearance. Pitfalls in experimental Aβ brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD. PMID:20854368

  7. 33 CFR 151.1508 - Revocation of clearance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Revocation of clearance. 151.1508 Section 151.1508 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) POLLUTION VESSELS CARRYING OIL, NOXIOUS LIQUID SUBSTANCES, GARBAGE, MUNICIPAL OR COMMERCIAL WASTE,...

  8. 5 CFR 720.307 - Interagency report clearance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Interagency report clearance. 720.307 Section 720.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) AFFIRMATIVE EMPLOYMENT PROGRAMS Disabled Veterans Affirmative Action Program §...

  9. 5 CFR 720.307 - Interagency report clearance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Interagency report clearance. 720.307 Section 720.307 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) AFFIRMATIVE EMPLOYMENT PROGRAMS Disabled Veterans Affirmative Action Program §...

  10. 7 CFR 1927.55 - Title clearance services.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 12 2014-01-01 2013-01-01 true Title clearance services. 1927.55 Section 1927.55... acquired by assumption or with loan funds, or involving the borrower or the seller exist; (5) If a water right is to be included in the security for the loan, and if so, the full legal description of the...

  11. Some Proposals Regarding Copyright Clearance and Digitisation in Higher Education.

    ERIC Educational Resources Information Center

    Bide, Mark; Oppenheim, Charles; Ramsden, Anne

    1997-01-01

    Examines issues of copyright clearance by British universities for digitizing published printed materials. Discusses types of digitization, pricing, contract language, "compliance culture," publishers' rights, terms of licenses, and developing a publishers'"code of practice," and proposes a matrix of uses and users to support consistent clearance…

  12. 49 CFR Appendix F to Part 512 - OMB Clearance

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 6 2010-10-01 2010-10-01 false OMB Clearance F Appendix F to Part 512 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONFIDENTIAL BUSINESS INFORMATION Pt. 512, App. F Appendix F to...

  13. Celllular Uptake and Clearance of TIO2 Nanoparticles

    EPA Science Inventory

    Differential rates of cellular uptake and clearance of engineered nanomaterials may influence the propensity for tissue accumulation under chronic exposure conditions. A retinal pigment epithelial cell line (ARPE-19) was used to investigate 1) if Ti02 (Degussa, P25) nanoparticles...

  14. 23 CFR Appendix B to Part 1327 - OMB Clearance

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false OMB Clearance B Appendix B to Part 1327 Highways NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURES FOR PARTICIPATING IN AND RECEIVING INFORMATION FROM THE NATIONAL DRIVER REGISTER PROBLEM DRIVER POINTER SYSTEM Pt....

  15. Influence of clearance model on numerical simulation of centrifugal pump

    NASA Astrophysics Data System (ADS)

    Wang, Z.; Gao, B.; Yang, L.; Du, W. Q.

    2016-05-01

    Computing models are always simplified to save the computing resources and time. Particularly, the clearance that between impeller and pump casing is always ignored. But the completer model is, the more precise result of numerical simulation is in theory. This paper study the influence of clearance model on numerical simulation of centrifugal pump. We present such influence via comparing performance, flow characteristic and pressure pulsation of two cases that the one of two cases is the model pump with clearance and the other is not. And the results show that the head decreases and power increases so that efficiency decreases after computing with front and back cavities. Then no-leakage model would improve absolute velocity magnitude in order to reach the rated flow rate. Finally, more disturbance induced by front cavity flow and wear-ring flow would change the pressure pulsation of impeller and volute. The performance of clearance flow is important for the whole pump in performance, flow characteristic, pressure pulsation and other respects.

  16. OMB Forms Clearance: Restrictions on Educational Research Plans.

    ERIC Educational Resources Information Center

    Coan, Donald L.

    Forms Clearance standards and regulations are used by the Office of Management and Budget and by the Education Division of the Department of Health, Education and Welfare in order to upgrade the quality of federal data collection, to minimize cost, minimize reporting burden, maximize utility, and to protect the privacy rights of respondents.…

  17. 10 CFR 95.17 - Processing facility clearance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.17 Processing facility clearance. (a...— (1) A determination based on review and approval of a Standard Practice Procedures Plan that granting... acceptable security review conducted by the NRC; (3) Submitting key management personnel for...

  18. 14 CFR 27.411 - Ground clearance: tail rotor guard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Ground clearance: tail rotor guard. 27.411 Section 27.411 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: NORMAL CATEGORY ROTORCRAFT Strength Requirements Control Surface...

  19. Seal Investigations of an Active Clearance Control System Concept

    NASA Technical Reports Server (NTRS)

    Steinetz, Bruce M.; Taylor, Shawn; Oswald, Jay; DeCastro, Jonathan A.

    2006-01-01

    In an effort to improve upon current thermal active clearance control methods, a first generation, fast-acting mechanically actuated, active clearance control system has been designed and installed into a non-rotating test rig. In order to harvest the benefit of tighter blade tip clearances, low-leakage seals are required for the actuated carrier segments of the seal shroud to prevent excessive leakage of compressor discharge (P3) cooling air. The test rig was designed and fabricated to facilitate the evaluation of these types of seals, identify seal leakage sources, and test other active clearance control system concepts. The objective of this paper is to present both experimental and analytical investigations into the nature of the face-seal to seal-carrier interface. Finite element analyses were used to examine face seal contact pressures and edge-loading under multiple loading conditions, varied E-seal positions and two new face seal heights. The analyses indicated that moving the E-seal inward radially and reducing face seal height would lead to more uniform contact conditions between the face seal and the carriers. Lab testing confirmed that moving the balance diameter inward radially caused a decrease in overall system leakage.

  20. 48 CFR 801.602-76 - Business clearance review.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Business clearance review. 801.602-76 Section 801.602-76 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS GENERAL DEPARTMENT OF VETERANS AFFAIRS ACQUISITION REGULATION SYSTEM Career Development, Contracting Authority, and Responsibilities...