Controlling feeding behavior by chemical or gene-directed targeting in the brain: what's so spatial about our methods?

PubMed Central

Khan, Arshad M.

2013-01-01

Intracranial chemical injection (ICI) methods have been used to identify the locations in the brain where feeding behavior can be controlled acutely. Scientists conducting ICI studies often document their injection site locations, thereby leaving kernels of valuable location data for others to use to further characterize feeding control circuits. Unfortunately, this rich dataset has not yet been formally contextualized with other published neuroanatomical data. In particular, axonal tracing studies have delineated several neural circuits originating in the same areas where ICI injection feeding-control sites have been documented, but it remains unclear whether these circuits participate in feeding control. Comparing injection sites with other types of location data would require careful anatomical registration between the datasets. Here, a conceptual framework is presented for how such anatomical registration efforts can be performed. For example, by using a simple atlas alignment tool, a hypothalamic locus sensitive to the orexigenic effects of neuropeptide Y (NPY) can be aligned accurately with the locations of neurons labeled by anterograde tracers or those known to express NPY receptors or feeding-related peptides. This approach can also be applied to those intracranial “gene-directed” injection (IGI) methods (e.g., site-specific recombinase methods, RNA expression or interference, optogenetics, and pharmacosynthetics) that involve viral injections to targeted neuronal populations. Spatial alignment efforts can be accelerated if location data from ICI/IGI methods are mapped to stereotaxic brain atlases to allow powerful neuroinformatics tools to overlay different types of data in the same reference space. Atlas-based mapping will be critical for community-based sharing of location data for feeding control circuits, and will accelerate our understanding of structure-function relationships in the brain for mammalian models of obesity and metabolic disorders. PMID:24385950

BEAM TRANSPORT LINES FOR THE BSNS.

DOE Office of Scientific and Technical Information (OSTI.GOV)

WEI, J.

2006-06-26

This paper presents the design of two beam transport lines at the BSNS: one is the injection line from the Linac to the RCS and the other is the target line from the RCS to the target station. In the injection beam line, space charge effects, transverse halo collimation, momentum tail collimation and debunching are the main concerned topics. A new method of using triplet cells and stripping foils is used to collimate transverse halo. A long straight section is reserved for the future upgrading linac and debuncher. In the target beam line, large halo emittance, beam stability at themore » target due to kicker failures and beam jitters, shielding of back-scattering neutrons from the target are main concerned topics. Special bi-gap magnets will be used to reduce beam losses in the collimators in front of the target.« less

Use of Protein G Microcolumns in Chromatographic Immunoassays: A Comparison of Competitive Binding Formats

PubMed Central

Pfaunmiller, Erika L.; Anguizola, Jeanethe A.; Milanuk, Mitchell L.; Carter, NaTasha; Hage, David S.

2016-01-01

Affinity microcolumns containing protein G were used as general platforms for creating chromatographic-based competitive binding immunoassays. Human serum albumin (HSA) was used as a model target for this work and HSA tagged with a near infrared fluorescent dye was utilized as the label. The protein G microcolumns were evaluated for use in several assay formats, including both solution-based and column-based competitive binding immunoassays and simultaneous or sequential injection formats. All of these methods were characterized by using the same amounts of labeled HSA and anti-HSA antibodies per sample, as chosen for the analysis of a protein target in the low-to-mid ng/mL range. The results were used to compare these formats in terms of their response, precision, limits of detection, and analysis time. All these methods gave detection limits in the range of 8–19 ng/mL and precisions ranging from ± 5% to ± 10% when using an injection flow rate of 0.10 mL/min. The column-based sequential injection immunoassay provided the best limit of detection and the greatest change in response at low target concentrations, while the solution-based simultaneous injection method had the broadest linear and dynamic ranges. These results provided valuable guidelines that can be employed to develop and extend the use of protein G microcolumns and these competitive binding formats to other protein biomarkers or biological agents of clinical or pharmaceutical interest. PMID:26777776

Intraperitoneal AAV9-shRNA inhibits target expression in neonatal skeletal and cardiac muscles.

PubMed

Mayra, Azat; Tomimitsu, Hiroyuki; Kubodera, Takayuki; Kobayashi, Masaki; Piao, Wenying; Sunaga, Fumiko; Hirai, Yukihiko; Shimada, Takashi; Mizusawa, Hidehiro; Yokota, Takanori

2011-02-11

Systemic injections of AAV vectors generally transduce to the liver more effectively than to cardiac and skeletal muscles. The short hairpin RNA (shRNA)-expressing AAV9 (shRNA-AAV9) can also reduce target gene expression in the liver, but not enough in cardiac or skeletal muscles. Higher doses of shRNA-AAV9 required for inhibiting target genes in cardiac and skeletal muscles often results in shRNA-related toxicity including microRNA oversaturation that can induce fetal liver failure. In this study, we injected high-dose shRNA-AAV9 to neonates and efficiently silenced genes in cardiac and skeletal muscles without inducing liver toxicity. This is because AAV is most likely diluted or degraded in the liver than in cardiac or skeletal muscle during cell division after birth. We report that this systemically injected shRNA-AAV method does not induce any major side effects, such as liver dysfunction, and the dose of shRNA-AAV is sufficient for gene silencing in skeletal and cardiac muscle tissues. This novel method may be useful for generating gene knockdown in skeletal and cardiac mouse tissues, thus providing mouse models useful for analyzing diseases caused by loss-of-function of target genes. Copyright © 2011 Elsevier Inc. All rights reserved.

Development of RNAi methods for Peregrinus maidis, the corn planthopper.

PubMed

Yao, Jianxiu; Rotenberg, Dorith; Afsharifar, Alireza; Barandoc-Alviar, Karen; Whitfield, Anna E

2013-01-01

The corn planthopper, Peregrinus maidis, is a major pest of agronomically-important crops. Peregrinus maidis has a large geographical distribution and transmits Maize mosaic rhabdovirus (MMV) and Maize stripe tenuivirus (MSpV). The objective of this study was to develop effective RNAi methods for P. maidis. Vacuolar-ATPase (V-ATPase) is an essential enzyme for hydrolysis of ATP and for transport of protons out of cells thereby maintaining membrane ion balance, and it has been demonstrated to be an efficacious target for RNAi in other insects. In this study, two genes encoding subunits of P. maidis V-ATPase (V-ATPase B and V-ATPase D) were chosen as RNAi target genes. The open reading frames of V-ATPase B and D were generated and used for constructing dsRNA fragments. Experiments were conducted using oral delivery and microinjection of V-ATPase B and V-ATPase D dsRNA to investigate the effectiveness of RNAi in P. maidis. Real-time quantitative reverse transcriptase-PCR (qRT-PCR) analysis indicated that microinjection of V-ATPase dsRNA led to a minimum reduction of 27-fold in the normalized abundance of V-ATPase transcripts two days post injection, while ingestion of dsRNA resulted in a two-fold reduction after six days of feeding. While both methods of dsRNA delivery resulted in knockdown of target transcripts, the injection method was more rapid and effective. The reduction in V-ATPase transcript abundance resulted in observable phenotypes. Specifically, the development of nymphs injected with 200 ng of either V-ATPase B or D dsRNA was impaired, resulting in higher mortality and lower fecundity than control insects injected with GFP dsRNA. Microscopic examination of these insects revealed that female reproductive organs did not develop normally. The successful development of RNAi in P. maidis to target specific genes will enable the development of new insect control strategies and functional analysis of vital genes and genes associated with interactions between P. maidis and MMV.

Polarized deuterium internal target at AmPS (NIKHEF)

NASA Astrophysics Data System (ADS)

Ferro-Luzzi, M.; Zhou, Z.-L.; van den Brand, J. F. J.; Bulten, H. J.; Alarcon, R.; van Bakel, N.; Botto, T.; Bouwhuis, M.; van Buuren, L.; Comfort, J.; Doets, M.; Dolfini, S.; Ent, R.; Geurts, D.; Heimberg, P.; Higinbotham, D. W.; de Jager, C. W.; Lang, J.; de Lange, D. J.; Norum, B.; Passchier, I.; Poolman, H. R.; Six, E.; Steijger, J.; Szczerba, D.; Unal, O.; de Vries, H.

1998-01-01

We describe the polarized deuterium target internal to the NIKHEF medium-energy electron storage ring. Tensor polarized deuterium was produced in an atomic beam source and injected into a storage cell target. A Breit-Rabi polarimeter was used to monitor the injected atomic beam intensity and polarization. An electrostatic ion-extraction system and a Wien filter were utilized to measure on-line the atomic fraction of the target gas in the storage cell. This device was supplemented with a tensor polarization analyzer using the neutron anisotropy of the 3H(d,n)α reaction at 60 keV. This method allows determining the density-averaged nuclear polarization of the target gas, independent of spatial and temporal variations. We address issues important for polarized hydrogen/deuterium internal targets, such as the effects of spin-exchange collisions and resonant transitions induced by the RF fields of the charged particle beam.

Polarized deuterium internal target at AmPS (NIKHEF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferro-Luzzi, M.; NIKHEF, P.O. Box 41882, 1009 DB Amsterdam; Zhou, Z.-L.

1998-01-20

We describe the polarized deuterium target internal to the NIKHEF medium-energy electron storage ring. Tensor polarized deuterium was produced in an atomic beam source and injected into a storage cell target. A Breit-Rabi polarimeter was used to monitor the injected atomic beam intensity and polarization. An electrostatic ion-extraction system and a Wien filter were utilized to measure on-line the atomic fraction of the target gas in the storage cell. This device was supplemented with a tensor polarization analyzer using the neutron anisotropy of the {sup 3}H(d,n){alpha} reaction at 60 keV. This method allows determining the density-averaged nuclear polarization of themore » target gas, independent of spatial and temporal variations. We address issues important for polarized hydrogen/deuterium internal targets, such as the effects of spin-exchange collisions and resonant transitions induced by the RF fields of the charged particle beam.« less

Real-time ultrasound image classification for spine anesthesia using local directional Hadamard features.

PubMed

Pesteie, Mehran; Abolmaesumi, Purang; Ashab, Hussam Al-Deen; Lessoway, Victoria A; Massey, Simon; Gunka, Vit; Rohling, Robert N

2015-06-01

Injection therapy is a commonly used solution for back pain management. This procedure typically involves percutaneous insertion of a needle between or around the vertebrae, to deliver anesthetics near nerve bundles. Most frequently, spinal injections are performed either blindly using palpation or under the guidance of fluoroscopy or computed tomography. Recently, due to the drawbacks of the ionizing radiation of such imaging modalities, there has been a growing interest in using ultrasound imaging as an alternative. However, the complex spinal anatomy with different wave-like structures, affected by speckle noise, makes the accurate identification of the appropriate injection plane difficult. The aim of this study was to propose an automated system that can identify the optimal plane for epidural steroid injections and facet joint injections. A multi-scale and multi-directional feature extraction system to provide automated identification of the appropriate plane is proposed. Local Hadamard coefficients are obtained using the sequency-ordered Hadamard transform at multiple scales. Directional features are extracted from local coefficients which correspond to different regions in the ultrasound images. An artificial neural network is trained based on the local directional Hadamard features for classification. The proposed method yields distinctive features for classification which successfully classified 1032 images out of 1090 for epidural steroid injection and 990 images out of 1052 for facet joint injection. In order to validate the proposed method, a leave-one-out cross-validation was performed. The average classification accuracy for leave-one-out validation was 94 % for epidural and 90 % for facet joint targets. Also, the feature extraction time for the proposed method was 20 ms for a native 2D ultrasound image. A real-time machine learning system based on the local directional Hadamard features extracted by the sequency-ordered Hadamard transform for detecting the laminae and facet joints in ultrasound images has been proposed. The system has the potential to assist the anesthesiologists in quickly finding the target plane for epidural steroid injections and facet joint injections.

Percutaneous foot joint needle placement using a C-arm flat-panel detector CT.

PubMed

Wiewiorski, Martin; Takes, Martin Thanh Long; Valderrabano, Victor; Jacob, Augustinus Ludwig

2012-03-01

Image guidance is valuable for diagnostic injections in foot orthopaedics. Flat-detector computed tomography (FD-CT) was implemented using a C-arm, and the system was tested for needle guidance in foot joint injections. FD-CT-guided joint infiltration was performed in 6 patients referred from the orthopaedic department for diagnostic foot injections. All interventions were performed utilising a flat-panel fluoroscopy system utilising specialised image guidance and planning software. Successful infiltration was defined by localisation of contrast media depot in the targeted joint. The pre- and post-interventional numeric analogue scale (NAS) pain score was assessed. All injections were technically successful. Contrast media deposit was documented in all targeted joints. Significant relief of symptoms was noted by all 6 participants. FD-CT-guided joint infiltration is a feasible method for diagnostic infiltration of midfoot and hindfoot joints. The FD-CT approach may become an alternative to commonly used 2D-fluoroscopically guidance.

Why are US women not using long-acting contraceptives?

PubMed

Tanfer, K; Wierzbicki, S; Payn, B

2000-01-01

Given the level of unintended pregnancy in the United States, it is somewhat surprising that hormonal implants and injectables-methods that are long-acting, reversible, highly effective and convenient--have not attained the popularity enjoyed by other medical methods. Knowing the reasons why women have so far spurned these methods might lead to the design and implementation of interventions and targeted social marketing to promote their use. Data from the 1993 and 1995 rounds of the National Survey of Women are used to examine the reasons women gave for not having used the implant or injectables, whether they intended to use these methods and how their attitudes toward them may influence their decision to use such methods in the future. Logistic regression models were used to identify the social and demographic characteristics that influence women's decisions not to use these methods. Fewer than 2% of women who were at risk of an unintended pregnancy in 1995 were using the implant, and under 3% were using the injectable. Women gave three major reasons for not using either of these methods: lack of knowledge; fear of side effects or health hazards; and satisfaction with the method they were currently using. Age, education, marital status, parity and current contraceptive method strongly predicted fear of side effects, lack of knowledge and satisfaction with the current method as reasons for not using the implant or the injectable. For example, women aged 30 or older and those with a college education were half as likely as younger women and those with no college education to mention fear of side effects as their main reason for not using the implant. Likewise, single women, women with one or more children and those using a barrier method were 2-3 times as likely as married women, childless women and those using a medical method to attribute nonuse to the implant's side effects. Few women said they intended to use these methods in the next 12 months: 5% for the implant and 10% for the injectable. Single women, women with no college education, women with children, women wanting to have a child (or another child) and women with positive attitudes toward the effect of using an injectable were significantly more likely to say they intended to use the injectable. Nevertheless, substantial proportions of women reported quite negative attitudes about these methods. The low prevalence of use and the low level of use intention for the implant and for injectables raise questions about the promise for the future of these methods. Each method seems to appeal to certain subgroups of women, however. Thus, if proper interventions and social marketing are targeted to such groups, they may be disabused of misperceptions regarding these methods and possibly become more willing to try them.

Joint inversion of time-lapse VSP data for monitoring CO2 injection at the Farnsworth EOR field in Texas

NASA Astrophysics Data System (ADS)

Zhang, M.; Gao, K.; Balch, R. S.; Huang, L.

2016-12-01

During the Development Phase (Phase III) of the U.S. Southwest Regional Partnership on Carbon Sequestration (SWP), time-lapse 3D vertical seismic profiling (VSP) data were acquired to monitor CO2 injection/migration at the Farnsworth Enhanced Oil Recovery (EOR) field, in partnership with the industrial partner Chaparral Energy. The project is to inject a million tons of carbon dioxide into the target formation, the deep oil-bearing Morrow Formation in the Farnsworth Unit EOR field. Quantitative time-lapse seismic monitoring has the potential to track CO2 movement in geologic carbon storage sites. Los Alamos National Laboratory (LANL) has recently developed new full-waveform inversion methods to jointly invert time-lapse seismic data for changes in elastic and anisotropic parameters in target monitoring regions such as a CO2 reservoir. We apply our new joint inversion methods to time-lapse VSP data acquired at the Farnsworth EOR filed, and present some preliminary results showing geophysical properties changes in the reservoir.

Delivery of RNAi reagents in murine models of obesity and diabetes.

PubMed

Wilcox, Denise M; Yang, Ruojing; Morgan, Sherry J; Nguyen, Phong T; Voorbach, Martin J; Jung, Paul M; Haasch, Deanna L; Lin, Emily; Bush, Eugene N; Opgenorth, Terry J; Jacobson, Peer B; Collins, Christine A; Rondinone, Cristina M; Surowy, Terry; Landschulz, Katherine T

2006-11-29

RNA interference (RNAi) is an exciting new tool to effect acute in vivo knockdown of genes for pharmacological target validation. Testing the application of this technology to metabolic disease targets, three RNAi delivery methods were compared in two frequently utilized preclinical models of obesity and diabetes, the diet-induced obese (DIO) and B6.V-Lep/J (ob/ob) mouse. Intraperitoneal (i.p.) and high pressure hydrodynamic intravenous (i.v.) administration of naked siRNA, and low pressure i.v. administration of shRNA-expressing adenovirus were assessed for both safety and gene knockdown efficacy using constructs targeting cJun N-terminal kinase 1 (JNK1). Hydrodynamic delivery of siRNA lowered liver JNK1 protein levels 40% in DIO mice, but was accompanied by iatrogenic liver damage. The ob/ob model proved even more intolerant of this technique, with hydrodynamic delivery resulting in severe liver damage and death of most animals. While well-tolerated, i.p. injections of siRNA in DIO mice did not result in any knockdown or phenotypic changes in the mice. On the other hand, i.v. injected adenovirus expressing shRNA potently reduced expression of JNK1 in vivo by 95% without liver toxicity. In conclusion, i.p. and hydrodynamic injections of siRNA were ineffective and/or inappropriate for in vivo gene targeting in DIO and ob/ob mice, while adenovirus-mediated delivery of shRNA provided a relatively benign and effective method for exploring liver target silencing.

A Cooperative Approach to Virtual Machine Based Fault Injection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naughton III, Thomas J; Engelmann, Christian; Vallee, Geoffroy R

Resilience investigations often employ fault injection (FI) tools to study the effects of simulated errors on a target system. It is important to keep the target system under test (SUT) isolated from the controlling environment in order to maintain control of the experiement. Virtual machines (VMs) have been used to aid these investigations due to the strong isolation properties of system-level virtualization. A key challenge in fault injection tools is to gain proper insight and context about the SUT. In VM-based FI tools, this challenge of target con- text is increased due to the separation between host and guest (VM).more » We discuss an approach to VM-based FI that leverages virtual machine introspection (VMI) methods to gain insight into the target s context running within the VM. The key to this environment is the ability to provide basic information to the FI system that can be used to create a map of the target environment. We describe a proof- of-concept implementation and a demonstration of its use to introduce simulated soft errors into an iterative solver benchmark running in user-space of a guest VM.« less

Polarized deuterium internal target at AmPS (NIKHEF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Norum, Blaine; De Jager, Cornelis; Geurts, D.

1997-08-01

We describe the polarized deuterium target internal to the NIKHEF medium-energy electron storage ring. Tensor polarized deuterium was produced in an atomic beam source and injected into a storage cell target. A Breit-Rabi polarimeter was used to monitor the injected atomic beam intensity and polarization. An electrostatic ion-extraction system and a Wien filter were utilized to measure on-line the atomic fraction of the target gas in the storage cell. This device was supplemented with a tensor polarization analyzer using the neutron anisotropy of the 3H(d,n)sigma reaction at 60 keV. This method allows determining the density-averaged nuclear polarization of the targetmore » gas, independent of spatial and temporal variations. We address issues important for polarized hydrogen/deuterium internal targets, such as the effects of spin-exchange collisions and resonant transitions induced by the RF fields of the charged particle beam.« less

Integrated vacuum absorption steam cycle gas separation

DOEpatents

Chen, Shiaguo [Champaign, IL; Lu, Yonggi [Urbana, IL; Rostam-Abadi, Massoud [Champaign, IL

2011-11-22

Methods and systems for separating a targeted gas from a gas stream emitted from a power plant. The gas stream is brought into contact with an absorption solution to preferentially absorb the targeted gas to be separated from the gas stream so that an absorbed gas is present within the absorption solution. This provides a gas-rich solution, which is introduced into a stripper. Low pressure exhaust steam from a low pressure steam turbine of the power plant is injected into the stripper with the gas-rich solution. The absorbed gas from the gas-rich solution is stripped in the stripper using the injected low pressure steam to provide a gas stream containing the targeted gas. The stripper is at or near vacuum. Water vapor in a gas stream from the stripper is condensed in a condenser operating at a pressure lower than the stripper to concentrate the targeted gas. Condensed water is separated from the concentrated targeted gas.

Focusing of light energy inside a scattering medium by controlling the time-gated multiple light scattering

NASA Astrophysics Data System (ADS)

Jeong, Seungwon; Lee, Ye-Ryoung; Choi, Wonjun; Kang, Sungsam; Hong, Jin Hee; Park, Jin-Sung; Lim, Yong-Sik; Park, Hong-Gyu; Choi, Wonshik

2018-05-01

The efficient delivery of light energy is a prerequisite for the non-invasive imaging and stimulating of target objects embedded deep within a scattering medium. However, the injected waves experience random diffusion by multiple light scattering, and only a small fraction reaches the target object. Here, we present a method to counteract wave diffusion and to focus multiple-scattered waves at the deeply embedded target. To realize this, we experimentally inject light into the reflection eigenchannels of a specific flight time to preferably enhance the intensity of those multiple-scattered waves that have interacted with the target object. For targets that are too deep to be visible by optical imaging, we demonstrate a more than tenfold enhancement in light energy delivery in comparison with ordinary wave diffusion cases. This work will lay a foundation to enhance the working depth of imaging, sensing and light stimulation.

Investigation of Alternative Return Strategies for Orion Trans-earth Injection Design Options

NASA Technical Reports Server (NTRS)

Marchand, Belinda G.; Scarritt, Sara K.; Howell, Kathleen C.; Weeks, Michael W.

2010-01-01

The purpose of this study is to investigate alternative return strategies for the Orion trans-Earth injection (TEI) phase. A dynamical systems analysis approach considers the structure of the stable and unstable Sun perturbed Earth-Moon manifolds near the Earth-Moon interface region. A hybrid approach, then, combines the results from this analysis with classical two-body methods in a targeting process that seeks to expand the window of return opportunities in a precision entry scenario. The resulting startup arcs can be used, for instance, to enhance the block set of solutions available onboard during an autonomous targeting process.

Design of a Coupled Thermoresponsive Hydrogel and Robotic System for Postinfarct Biomaterial Injection Therapy.

PubMed

Zhu, Yang; Wood, Nathan A; Fok, Kevin; Yoshizumi, Tomo; Park, Dae Woo; Jiang, Hongbin; Schwartzman, David S; Zenati, Marco A; Uchibori, Takafumi; Wagner, William R; Riviere, Cameron N

2016-09-01

In preclinical testing, ventricular wall injection of hydrogels has been shown to be effective in modulating ventricular remodeling and preserving cardiac function. For some approaches, early-stage clinical trials are under way. The hydrogel delivery method varies, with minimally invasive approaches being preferred. Endocardial injections carry a risk of hydrogel regurgitation into the circulation, and precise injection patterning is a challenge. An epicardial approach with a thermally gelling hydrogel through the subxiphoid pathway overcomes these disadvantages. A relatively stiff, thermally responsive, injectable hydrogel based on N-isopropylacrylamide and N-vinylpyrrolidone (VP gel) was synthesized and characterized. VP gel thermal behavior was tuned to couple with a transepicardial injection robot, incorporating a cooling feature to achieve injectability. Ventricular wall injections of the optimized VP gel have been performed ex vivo and on beating porcine hearts. Thermal transition temperature, viscosity, and gelling time for the VP gel were manipulated by altering N-vinylpyrrolidone content. The target parameters for cooling in the robotic system were chosen by thermal modeling to support smooth, repeated injections on an ex vivo heart. Injections at predefined locations and depth were confirmed in an infarcted porcine model. A coupled thermoresponsive hydrogel and robotic injection system incorporating a temperature-controlled injectate line was capable of targeted injections and amenable to use with a subxiphoid transepicardial approach for hydrogel injection after myocardial infarction. The confirmation of precise location and depth injections would facilitate a patient-specific planning strategy to optimize injection patterning to maximize the mechanical benefits of hydrogel placement. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Targeted gene delivery in the cricket brain, using in vivo electroporation.

PubMed

Matsumoto, Chihiro Sato; Shidara, Hisashi; Matsuda, Koji; Nakamura, Taro; Mito, Taro; Matsumoto, Yukihisa; Oka, Kotaro; Ogawa, Hiroto

2013-12-01

The cricket (Gryllus bimaculatus) is a hemimetabolous insect that is emerging as a model organism for the study of neural and molecular mechanisms of behavioral traits. However, research strategies have been limited by a lack of genetic manipulation techniques that target the nervous system of the cricket. The development of a new method for efficient gene delivery into cricket brains, using in vivo electroporation, is described here. Plasmid DNA, which contained an enhanced green fluorescent protein (eGFP) gene, under the control of a G. bimaculatus actin (Gb'-act) promoter, was injected into adult cricket brains. Injection was followed by electroporation at a sufficient voltage. Expression of eGFP was observed within the brain tissue. Localized gene expression, targeted to specific regions of the brain, was also achieved using a combination of local DNA injection and fine arrangement of the electroporation electrodes. Further studies using this technique will lead to a better understanding of the neural and molecular mechanisms that underlie cricket behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Simultaneous quantification of tumor uptake for targeted and non-targeted liposomes and their encapsulated contents by ICP-MS

PubMed Central

Cheng, Zhiliang; Zaki, Ajlan Al; Hui, James Z; Tsourkas, Andrew

2012-01-01

Liposomes are intensively being developed for biomedical applications including drug and gene delivery. However, targeted liposomal delivery in cancer treatment is a very complicated multi-step process. Unfavorable liposome biodistribution upon intravenous administration and membrane destabilization in blood circulation could result in only a very small fraction of cargo reaching the tumors. It would therefore be desirable to develop new quantitative strategies to track liposomal delivery systems to improve the therapeutic index and decrease systemic toxicity. Here, we developed a simple and non-radiative method to quantify the tumor uptake of targeted and non-targeted control liposomes as well as their encapsulated contents simultaneously. Specifically, four different chelated lanthanide metals were encapsulated or surface-conjugated onto tumor-targeted and non-targeted liposomes, respectively. The two liposome formulations were then injected into tumor-bearing mice simultaneously and their tumor delivery was determined quantitatively via inductively coupled plasma-mass spectroscopy (ICP-MS), allowing for direct comparisons. Tumor uptake of the liposomes themselves and their encapsulated contents were consistent with targeted and non-targeted liposome formulations that were injected individually. PMID:22882145

Intramyocardial Injection of siRNAs Can Efficiently Establish Myocardial Tissue-Specific Renalase Knockdown Mouse Model.

PubMed

Huang, Kun; Liu, Ju; Zhang, Hui; Wang, Jiliang; Li, Huili

2016-01-01

Ischaemia/reperfusion (I/R) injury will cause additional death of cardiomyocytes in ischaemic heart disease. Recent studies revealed that renalase was involved in the I/R injury. So, the myocardial tissue-specific knockdown mouse models were needed for the investigations of renalase. To establish the mouse models, intramyocardial injection of siRNAs targeting renalase was performed in mice. The wild distribution and high transfection efficiency of the siRNAs were approved. And the renalase expression was efficiently suppressed in myocardial tissue. Compared with the high cost, time consumption, and genetic compensation risk of the Cre/loxP technology, RNA interference (RNAi) technology is much cheaper and less time-consuming. Among the RNAi technologies, injection of siRNAs is safer than virus. And considering the properties of the I/R injury mouse models, the efficiency and durability of injection with siRNAs are acceptable for the studies. Altogether, intramyocardial injection of siRNAs targeting renalase is an economical, safe, and efficient method to establish myocardial tissue-specific renalase knockdown mouse models.

Large-volume injection of sample diluents not miscible with the mobile phase as an alternative approach in sample preparation for bioanalysis: an application for fenspiride bioequivalence.

PubMed

Medvedovici, Andrei; Udrescu, Stefan; Albu, Florin; Tache, Florentin; David, Victor

2011-09-01

Liquid-liquid extraction of target compounds from biological matrices followed by the injection of a large volume from the organic layer into the chromatographic column operated under reversed-phase (RP) conditions would successfully combine the selectivity and the straightforward character of the procedure in order to enhance sensitivity, compared with the usual approach of involving solvent evaporation and residue re-dissolution. Large-volume injection of samples in diluents that are not miscible with the mobile phase was recently introduced in chromatographic practice. The risk of random errors produced during the manipulation of samples is also substantially reduced. A bioanalytical method designed for the bioequivalence of fenspiride containing pharmaceutical formulations was based on a sample preparation procedure involving extraction of the target analyte and the internal standard (trimetazidine) from alkalinized plasma samples in 1-octanol. A volume of 75 µl from the octanol layer was directly injected on a Zorbax SB C18 Rapid Resolution, 50 mm length × 4.6 mm internal diameter × 1.8 µm particle size column, with the RP separation being carried out under gradient elution conditions. Detection was made through positive ESI and MS/MS. Aspects related to method development and validation are discussed. The bioanalytical method was successfully applied to assess bioequivalence of a modified release pharmaceutical formulation containing 80 mg fenspiride hydrochloride during two different studies carried out as single-dose administration under fasting and fed conditions (four arms), and multiple doses administration, respectively. The quality attributes assigned to the bioanalytical method, as resulting from its application to the bioequivalence studies, are highlighted and fully demonstrate that sample preparation based on large-volume injection of immiscible diluents has an increased potential for application in bioanalysis.

Targeted Delivery of Antiglaucoma Drugs to the Supraciliary Space Using Microneedles

PubMed Central

Kim, Yoo C.; Edelhauser, Henry F.; Prausnitz, Mark R.

2014-01-01

Purpose. In this work, we tested the hypothesis that highly targeted delivery of antiglaucoma drugs to the supraciliary space by using a hollow microneedle allows dramatic dose sparing of the drug compared to topical eye drops. The supraciliary space is the most anterior portion of the suprachoroidal space, located below the sclera and above the choroid and ciliary body. Methods. A single, hollow 33-gauge microneedle, 700 to 800 μm in length, was inserted into the sclera and used to infuse antiglaucoma drugs into the supraciliary space of New Zealand white rabbits (N = 3–6 per group). Sulprostone, a prostaglandin analog, and brimonidine, an α2-adrenergic agonist, were delivered via supraciliary and topical administration at various doses. The drugs were delivered unilaterally, and intraocular pressure (IOP) of both eyes was measured by rebound tonometry for 9 hours after injection to assess the pharmacodynamic responses. To assess safety of the supraciliary injection, IOP change immediately after intravitreal and supraciliary injection were compared. Results. Supraciliary delivery of both sulprostone and brimonidine reduced IOP by as much as 3 mm Hg bilaterally in a dose-related response; comparison with topical administration at the conventional human dose showed approximately 100-fold dose sparing by supraciliary injection for both drugs. A safety study showed that the kinetics of IOP elevation immediately after supraciliary and intravitreal injection of placebo formulations were similar. Conclusions. This study introduced the use of targeted drug delivery to the supraciliary space by using a microneedle and demonstrated dramatic dose sparing of antiglaucoma therapeutic agents compared to topical eye drops. Targeted delivery in this way can increase safety by reducing side effects and could allow a single injection to contain enough drug for long-term sustained delivery. PMID:25212782

Hollow Microneedles for Intradermal Injection Fabricated by Sacrificial Micromolding and Selective Electrodeposition

PubMed Central

Norman, James J.; Choi, Seong-O; Tong, Nhien T.; Aiyar, Avishek R.; Patel, Samirkumar R.; Prausnitz, Mark R.; Allen, Mark G.

2012-01-01

Limitations with standard intradermal injections have created a clinical need for an alternative, low-cost injection device. In this study, we designed a hollow metal microneedle for reliable intradermal injection and developed a high-throughput micromolding process to produce metal microneedles with complex geometries. To fabricate the microneedles, we laser-ablated a 70 μm × 70 μm square cavity near the tip of poly(lactic acid-co-glyoclic acid) (PLGA) microneedles. The master structure was a template for multiple micromolded PLGA replicas. Each replica was sputtered with a gold seed layer with minimal gold deposited in the cavity due to masking effects. In this way, nickel was electrodeposited selectively outside of the cavity, after which the polymer replica was dissolved to produce a hollow metal microneedle. Force-displacement tests showed the microneedles, with 12 μm thick electrodeposition, could penetrate skin with an insertion force 9 times less than their axial failure force. We injected fluid with the microneedles into pig skin in vitro and hairless guinea pig skin in vivo. The injections targeted 90% of the material within the skin with minimal leakage onto the skin surface. We conclude that hollow microneedles made by this simple microfabrication method can achieve targeted intradermal injection. PMID:23053452

Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates

PubMed Central

Jain, Meena; Doughty, Diane; Clawson, Corbin; Li, Xiaobai; White, Nicholas; Agoram, Balaji; van der Merwe, René

2017-01-01

Objective: Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. Methods: This phase I study randomized 60 healthy adults to receive 300 mg tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). Results: No differences in the PK profile of tralokinumab were observed between cohorts. Immediately following injection, injection-site pain intensity (mean (SD)) was lowest following 0.167 mL/min injection (5.1 mm (8.0) via visual analog scale (VAS)) and greatest following 12 mL/min injection (41 mm (27.7) via VAS); with mean injection-site pruritus intensity low for all participants. Two types of local injection-site reactions were observed: erythema (58.3%) and hematoma/bleeding (18.3%). All treatment-emergent adverse events were mild. Conclusions: Tralokinumab 300 mg is well tolerated, with comparable PK, when administered by a single 2-mL injection at different rates of subcutaneous injection vs. two 1-mL injections. PMID:28590244

Tild-CRISPR Allows for Efficient and Precise Gene Knockin in Mouse and Human Cells.

PubMed

Yao, Xuan; Zhang, Meiling; Wang, Xing; Ying, Wenqin; Hu, Xinde; Dai, Pengfei; Meng, Feilong; Shi, Linyu; Sun, Yun; Yao, Ning; Zhong, Wanxia; Li, Yun; Wu, Keliang; Li, Weiping; Chen, Zi-Jiang; Yang, Hui

2018-05-21

The targeting efficiency of knockin sequences via homologous recombination (HR) is generally low. Here we describe a method we call Tild-CRISPR (targeted integration with linearized dsDNA-CRISPR), a targeting strategy in which a PCR-amplified or precisely enzyme-cut transgene donor with 800-bp homology arms is injected with Cas9 mRNA and single guide RNA into mouse zygotes. Compared with existing targeting strategies, this method achieved much higher knockin efficiency in mouse embryos, as well as brain tissue. Importantly, the Tild-CRISPR method also yielded up to 12-fold higher knockin efficiency than HR-based methods in human embryos, making it suitable for studying gene functions in vivo and developing potential gene therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

A ferritin-containing nanoconjugate as MRI image-guidance to target Necl-5, a tumor-surface antigen: a potential thermal accelerant for microwave ablation

NASA Astrophysics Data System (ADS)

Park, William K. C.; Mills, David R.; Lim, Sierin; Sana, Barindra; Frank, Victoria E.; Kenyon, Brendan M.; Primmer, Michael P.; Paul, Jarod B.; Baird, Greyson L.; Walsh, Edward; Dupuy, Damian E.

2017-02-01

Purpose: A ferritin-containing nanoparticle conjugated with a target-specific antibody was investigated as a MRI contrast agent for tumor detection. A genetically modified ferritin to markedly improve Fe (III) payload (up to 7,000 Fe ions), was chemically tethered to a monoclonal antibody against rat Nectin-like molecule 5 (Necl-5). Necl-5 is a cell surface glycoprotein that is highly expressed on the cell surface of many common epithelial cancers, including prostate cancer. It was previously demonstrated that this novel nanoconjugate agent exhibited effective in vitro targeting of Necl- 5 expressing tumor cells and exhibited strong MRI contrast characteristics via shortening of T2. Here, we demonstrate that the nanoconjugate-Necl-5 interaction can be exploited to target and detect tumor in vivo by MRI. Procedure: Using an in vivo tumor model (i.e., tumor size 0.5-1 cm, immunodeficient beige/nude/xid mouse, xenograft injection with transformed rat prostate cells), efficacy of the conjugate targeting the tumor was examined. We used two injection strategies, a direct and a tail vein injection (0.8 mg, 300 μL per subject). Pre-injection baseline and postinjection scans were performed with the following spin-echo sequence parameters: Field of view = 90x53mm, reconstruction matrix size = 192x114, slice thickness = 1mm (10 slices), repetition time (TR) = 2070 ms, echo times (TE) = 11-198 ms in 11ms steps (18 echoes), number of averages = 2, acquisition time per scan = 7min 56s. Results: All T2 data obtained were converted to R2 for demonstration purposes (R2 = 1/T2). The tail vein injected conjugate significantly increased R2 response (22.9 +/- 5.2 s-1) as compared to control (13.5 +/-1.7 s-1) at 4 h. The weaker R2 increase was noted (15.2 +/- 2.0 s-1) at 24 h. No notable changes in R2 were observed in surrounding tissues regardless the stages of the measurement. We also measured the initial conjugate kinetics for both injection methods with respect to the ability of targeting the tumor. Direct injection of the nanoconjugate in to the center of the tumor showed a stronger and more rapid increase in R2 than the tail vein injection. Conclusion: The nanoconjugate interacts strongly and selectively in situ with Necl-5 overexpressing tumor cells. Direct injection of the nanoconjugate into the body of the tumor caused a more significant in situ R2 increase in MRI than the tail vein injection. Varying degrees of R2 increase within the tumor mass is likely to represent different distribution patterns of the conjugate, reflective of tumor heterogeneity.

Time series geophysical monitoring of permanganate injections and in situ chemical oxidation of PCE, OU1 area, Savage Superfund Site, Milford, NH, USA

NASA Astrophysics Data System (ADS)

Harte, Philip T.; Smith, Thor E.; Williams, John H.; Degnan, James R.

2012-05-01

In situ chemical oxidation (ISCO) treatment with sodium permanganate, an electrically conductive oxidant, provides a strong electrical signal for tracking of injectate transport using time series geophysical surveys including direct current (DC) resistivity and electromagnetic (EM) methods. Effective remediation is dependent upon placing the oxidant in close contact with the contaminated aquifer. Therefore, monitoring tools that provide enhanced tracking capability of the injectate offer considerable benefit to guide subsequent ISCO injections. Time-series geophysical surveys were performed at a superfund site in New Hampshire, USA over a one-year period to identify temporal changes in the bulk electrical conductivity of a tetrachloroethylene (PCE; also called tetrachloroethene) contaminated, glacially deposited aquifer due to the injection of sodium permanganate. The ISCO treatment involved a series of pulse injections of sodium permanganate from multiple injection wells within a contained area of the aquifer. After the initial injection, the permanganate was allowed to disperse under ambient groundwater velocities. Time series geophysical surveys identified the downward sinking and pooling of the sodium permanganate atop of the underlying till or bedrock surface caused by density-driven flow, and the limited horizontal spread of the sodium permanganate in the shallow parts of the aquifer during this injection period. When coupled with conventional monitoring, the surveys allowed for an assessment of ISCO treatment effectiveness in targeting the PCE plume and helped target areas for subsequent treatment.

Time series geophysical monitoring of permanganate injections and in situ chemical oxidation of PCE, OU1 area, Savage Superfund Site, Milford, NH, USA

USGS Publications Warehouse

Harte, Philip T.; Smith, Thor E.; Williams, John H.; Degnan, James R.

2012-01-01

In situ chemical oxidation (ISCO) treatment with sodium permanganate, an electrically conductive oxidant, provides a strong electrical signal for tracking of injectate transport using time series geophysical surveys including direct current (DC) resistivity and electromagnetic (EM) methods. Effective remediation is dependent upon placing the oxidant in close contact with the contaminated aquifer. Therefore, monitoring tools that provide enhanced tracking capability of the injectate offer considerable benefit to guide subsequent ISCO injections. Time-series geophysical surveys were performed at a superfund site in New Hampshire, USA over a one-year period to identify temporal changes in the bulk electrical conductivity of a tetrachloroethylene (PCE; also called tetrachloroethene) contaminated, glacially deposited aquifer due to the injection of sodium permanganate. The ISCO treatment involved a series of pulse injections of sodium permanganate from multiple injection wells within a contained area of the aquifer. After the initial injection, the permanganate was allowed to disperse under ambient groundwater velocities. Time series geophysical surveys identified the downward sinking and pooling of the sodium permanganate atop of the underlying till or bedrock surface caused by density-driven flow, and the limited horizontal spread of the sodium permanganate in the shallow parts of the aquifer during this injection period. When coupled with conventional monitoring, the surveys allowed for an assessment of ISCO treatment effectiveness in targeting the PCE plume and helped target areas for subsequent treatment.

Time series geophysical monitoring of permanganate injections and in situ chemical oxidation of PCE, OU1 area, Savage Superfund Site, Milford, NH, USA.

PubMed

Harte, Philip T; Smith, Thor E; Williams, John H; Degnan, James R

2012-05-01

In situ chemical oxidation (ISCO) treatment with sodium permanganate, an electrically conductive oxidant, provides a strong electrical signal for tracking of injectate transport using time series geophysical surveys including direct current (DC) resistivity and electromagnetic (EM) methods. Effective remediation is dependent upon placing the oxidant in close contact with the contaminated aquifer. Therefore, monitoring tools that provide enhanced tracking capability of the injectate offer considerable benefit to guide subsequent ISCO injections. Time-series geophysical surveys were performed at a superfund site in New Hampshire, USA over a one-year period to identify temporal changes in the bulk electrical conductivity of a tetrachloroethylene (PCE; also called tetrachloroethene) contaminated, glacially deposited aquifer due to the injection of sodium permanganate. The ISCO treatment involved a series of pulse injections of sodium permanganate from multiple injection wells within a contained area of the aquifer. After the initial injection, the permanganate was allowed to disperse under ambient groundwater velocities. Time series geophysical surveys identified the downward sinking and pooling of the sodium permanganate atop of the underlying till or bedrock surface caused by density-driven flow, and the limited horizontal spread of the sodium permanganate in the shallow parts of the aquifer during this injection period. When coupled with conventional monitoring, the surveys allowed for an assessment of ISCO treatment effectiveness in targeting the PCE plume and helped target areas for subsequent treatment. Published by Elsevier B.V.

Enabling skin vaccination using new delivery technologies

PubMed Central

Kim, Yeu-Chun; Prausnitz, Mark R.

2011-01-01

The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections, and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination. PMID:21799951

Enabling skin vaccination using new delivery technologies

PubMed Central

Kim, Yeu-Chun; Prausnitz, Mark R.

2011-01-01

The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination. PMID:21472533

Guiding intramuscular diaphragm injections using real-time ultrasound and electromyography.

PubMed

Sarwal, Aarti; Cartwright, Michael S; Mitchell, Erin; Williams, Koudy; Walker, Francis O; Childers, Martin K

2015-02-01

We describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals. Ultrasound was used to visualize the diaphragm on each side of spontaneously breathing, anesthetized beagle dogs and cynomolgus macaques. An electromyography (EMG) needle was introduced and directed by ultrasound to confirm that the needle entered the muscular portion of the diaphragm, and methylene blue was injected. Injection accuracy was confirmed upon necropsy by tracking the spread of methylene blue. All methylene blue injections were confirmed to have been placed appropriately into the diaphragm. This study demonstrates the feasibility and accuracy of using ultrasound and EMG to guide injections and to reduce complications associated with conventional blind techniques. Ultrasound guidance can be used for clinical EMG of the diaphragm. Future applications may include targeted diaphragm injections with gene replacement therapy in neuromuscular diseases. © 2014 Wiley Periodicals, Inc.

Replenishing data descriptors in a DMA injection FIFO buffer

DOEpatents

Archer, Charles J [Rochester, MN; Blocksome, Michael A [Rochester, MN; Cernohous, Bob R [Rochester, MN; Heidelberger, Philip [Cortlandt Manor, NY; Kumar, Sameer [White Plains, NY; Parker, Jeffrey J [Rochester, MN

2011-10-11

Methods, apparatus, and products are disclosed for replenishing data descriptors in a Direct Memory Access (`DMA`) injection first-in-first-out (`FIFO`) buffer that include: determining, by a messaging module on an origin compute node, whether a number of data descriptors in a DMA injection FIFO buffer exceeds a predetermined threshold, each data descriptor specifying an application message for transmission to a target compute node; queuing, by the messaging module, a plurality of new data descriptors in a pending descriptor queue if the number of the data descriptors in the DMA injection FIFO buffer exceeds the predetermined threshold; establishing, by the messaging module, interrupt criteria that specify when to replenish the injection FIFO buffer with the plurality of new data descriptors in the pending descriptor queue; and injecting, by the messaging module, the plurality of new data descriptors into the injection FIFO buffer in dependence upon the interrupt criteria.

Therapeutic effect for liver-metastasized tumor by sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA.

PubMed

Hattori, Yoshiyuki; Arai, Shohei; Kikuchi, Takuto; Ozaki, Kei-Ichi; Kawano, Kumi; Yonemochi, Etsuo

2016-04-01

Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of anionic polymer and cationic liposome/siRNA complex (cationic lipoplex). In this study, we investigated whether siRNA delivered by this sequential injection could significantly suppress mRNA expression of the targeted gene in liver metastasis and inhibit tumor growth. When cationic lipoplex was intravenously injected into mice bearing liver metastasis of human breast tumor MCF-7 at 1 min after intravenous injection of chondroitin sulfate C (CS) or poly-l-glutamic acid (PGA), siRNA was accumulated in tumor-metastasized liver. In terms of a gene silencing effect, sequential injections of CS or PGA plus cationic lipoplex of luciferase siRNA could reduce luciferase activity in liver MCF-7-Luc metastasis. Regarding the side effects, sequential injections of CS plus cationic lipoplex did not exhibit hepatic damage or induction of inflammatory cytokines in serum after repeated injections, but sequential injections of PGA plus cationic lipoplex did. Finally, sequential injections of CS plus cationic lipoplex of protein kinase N3 siRNA could suppress tumor growth in the mice bearing liver metastasis. From these findings, sequential injection of CS and cationic lipoplex of siRNA might be a novel systemic method of delivering siRNA to liver metastasis.

Migration rates and formation injectivity to determine containment time scales of sequestered carbon dioxide

USGS Publications Warehouse

Burke, Lauri

2012-01-01

Additionally, this research establishes a methodology to calculate the injectivity of a target formation. Because injectivity describes the pressure increase due to the introduction of fluids into a formation, the relevant application of injectivity is to determine the pressure increase, due to an injection volume and flow rate, that will induce fractures in the reservoir rocks. This quantity is defined mathematically as the maximum pressure differential between the hydrostatic gradient and the fracture gradient of the target formation. Injectivity is mathematically related to the maximum pressure differential of the formation, and can be used to determine the upper limit for the pressure increase that an injection target can withstand before fracturing.

OPTIMIZATION OF HIGH-SPEED GC/TOFMS FOR METHOD TO-14 ANALYSIS

EPA Science Inventory

A fast GC/MS system (FGCMS) consisting of a high-speed gas chromatograph equipped with a narrow bandwidth injection accessory and a time-of-flight mass spectrometer detector is being optimized for analysis of Method TO-14 target compounds. The system consists entirely of comm...

CRISPR/Cas9-based genome editing in mice by single plasmid injection.

PubMed

Fujihara, Yoshitaka; Ikawa, Masahito

2014-01-01

CRISPR/Cas-mediated genome modification has opened a new era for elucidating gene function. Gene knockout mice can be generated by injecting humanized Cas9 (hCas9) mRNA and guide RNA (sgRNA) into fertilized eggs. However, delivery of RNA instead of DNA to the fertilized oocyte requires extra preparation and extra care with storage. To simplify the method of delivery, we injected the circular pX330 plasmids expressing both hCas9 and sgRNA and found that mutant mice were generated as efficiently as with RNA injection. Different from the linearized plasmid, the circular plasmid decreased the chance of integration into the host genome. We also developed the pCAG-EGxxFP reporter plasmid for evaluating the sgRNA activity by observing EGFP fluorescence in HEK293T cells. The combination of these techniques allowed us to develop a rapid, easy, and reproducible strategy for targeted mutagenesis in living mice. This chapter provides an experimental protocol for the design of sgRNAs, the construction of pX330-sgRNA and pCAG-EGxxFP-target plasmids, the validation of cleavage efficiency in vitro, and the generation of targeted gene mutant mice. These mice can be generated within a month.

Targeted endomyocardial injections of therapeutic cells using x-ray fused with MRI guidance

NASA Astrophysics Data System (ADS)

Gutiérrez, Luis F.; de Silva, Ranil; McVeigh, Elliot R.; Ozturk, Cengizhan; Lederman, Robert J.

2006-03-01

The utility of X-ray fused with MRI (XFM) using external fiducial markers to perform targeted endomyocardial injections in infarcted hearts of swine was tested. Endomyocardial injections of feridex-labeled mesenchymal stromal cells (Fe-MSC) were performed in the previously infarcted hearts of 12 Yucatan miniswine (33-67 kg). Animals had pre-injection cardiac MRI, XFM-guided endomyocardial injection of Fe-MSC suspension spiked with tissue dye, and post-injection MRI. 24 hours later, after euthanasia, the hearts were excised, sliced and stained with TTC. During the injection procedure, operators were provided with 3D surfaces of endocardium, epicardium, myocardial wall thickness and infarct registered with live XF images to facilitate device navigation and choice of injection location. 130 injections were performed in hearts where diastolic wall thickness ranged from 2.6 to 17.7 mm. Visual inspection of the pattern of dye staining on TTC stained heart slices correlated (r=0.98) with XFM-derived injection locations mapped onto delayed hyperenhancement MRI and the susceptibility artifacts seen on the post-injection T2*-weighted gradient echo MRI. The in vivo target registration error was 3.17+/-2.61 mm (n=64) and 75% of injections were within 4 mm of the predicted location. 3D to 2D registration of XF and MR images using external fiducial markers enables accurate targeted endomyocardial injection in a swine model of myocardial infarction. The present data suggest that the safety and efficacy of this approach for performing targeted endomyocardial delivery should be evaluated further clinically.

Vascular targeting of a gold nanoparticle to breast cancer metastasis

PubMed Central

Peiris, Pubudu M.; Deb, Partha; Doolittle, Elizabeth; Doron, Gilad; Goldberg, Amy; Govender, Priya; Shah, Shruti; Rao, Swetha; Carbone, Sarah; Cotey, Thomas; Sylvestre, Meilyn; Singh, Sohaj; Schiemann, William P.; Lee, Zhenghong; Karathanasis, Efstathios

2015-01-01

The vast majority of breast cancer deaths are due to metastatic disease. While deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the gold nanoparticles, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Due to the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. PMID:26036431

Vascular Targeting of a Gold Nanoparticle to Breast Cancer Metastasis.

PubMed

Peiris, Pubudu M; Deb, Partha; Doolittle, Elizabeth; Doron, Gilad; Goldberg, Amy; Govender, Priya; Shah, Shruti; Rao, Swetha; Carbone, Sarah; Cotey, Thomas; Sylvestre, Meilyn; Singh, Sohaj; Schiemann, William P; Lee, Zhenghong; Karathanasis, Efstathios

2015-08-01

The vast majority of breast cancer deaths are due to metastatic disease. Although deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle (AuNP) to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the AuNPs, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Because of the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Fluoroscopy-Guided Sacroiliac Intraarticular Injection via the Middle Portion of the Joint.

PubMed

Kurosawa, Daisuke; Murakami, Eiichi; Aizawa, Toshimi

2017-09-01

Sacroiliac intraarticular injection is necessary to confirm sacroiliac joint (SIJ) pain and is usually performed via the caudal one-third portion of the joint. However, this is occasionally impossible for anatomical reasons, and the success rate is low in clinical settings. We describe a technique via the middle portion of the joint. Observational study. Enrolled were 69 consecutive patients (27 men and 42 women, with an average age of 53 years) in whom the middle portion of 100 joints was targeted. With the patient lying prone-oblique with the painful side down, a spinal needle was inserted into the middle portion of the joint. Subsequently, the fluoroscopy tube was angled at a caudal tilt of 25-30° to clearly detect the recess between the ilium and sacrum and the needle depth and direction. When the needle reached the posterior joint line, 2% lidocaine was injected after the contrast medium outlined the joint. The success rate of the injection method was 80% (80/100). Among 80 successful cases, four were previously unsuccessful when the conventional method was used. Intraarticular injection using the new technique was unsuccessful in 20 joints; in three of these cases, the conventional method proved successful, and no techniques were successful in the other 17 cases. The injection technique via the middle portion of the joint can overcome some of the difficulties of the conventional injection method and can improve the chances of successful intraarticular injection. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Assessment of injection safety in Ha Dong General Hospital, Hanoi, in 2012.

PubMed

Van Tuong, Phan; Phuong, Tran Thi Minh; Anh, Bui Thi My; Nguyen, Trang Huyen Thi

2017-01-01

Background : Injection is one of the most frequently used medical methods to introduce drugs or other substances into the body for purposes of treatment or prevention. Unsafe injection can cause adverse outcomes, such as abscess and anaphylactic shock, and increases the risk of blood-borne transmission of viruses to patients and health care workers, as well as the community. Recognizing the importance of injection safety, in 2000 the Vietnamese Ministry of Health (MOH) collaborated with the Vietnam Nurses Association to launch the "Safe injection" program throughout the country, including Hanoi. Methods : This cross-sectional study, combining quantitative and qualitative analysis, was conducted from February to August 2012 in Ha Dong General Hospital using a structured questionnaire and observation checklist. The target population of the study was 109 nurses working in clinical departments and 436 injections were observed. Results : The percentage of nurses who are familiar with injection safety standards was found to be 82.6%. The proportion of practical injections that met the 23 standards of injection safety set by the MOH amounted to 22.2%. The factors related to safe injection practice of nurses who were younger age group (OR=3.1; p<0.05) and fewer number of years working as a nurse (OR=2.8; p<0.05). Conclusions : While nurses have high level of knowledge about safe injections but a small proportion actually practiced. Experience may not always guarantee safe practices.  Injection safety training should be regularly imparted upon all categories of nurses.

Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects

PubMed Central

Lei, Yang; Nosoudi, Nasim; Vyavahare, Naren

2014-01-01

Background and aims Elastin-specific medial arterial calcification (MAC) is an arterial disease commonly referred as Monckeberg’s sclerosis. It causes significant arterial stiffness, and as yet, no clinical therapy exists to prevent or reverse it. We developed albumin nanoparticles (NPs) loaded with disodium ethylene diaminetetraacetic acid (EDTA) that were designed to target calcified elastic lamina when administrated by intravenous injection. Methods and Results We optimized NP size, charge, and EDTA-loading efficiency (150~200 nm, zeta potential of − 22.89 ~ − 31.72 mV, loading efficiency for EDTA ~20 %) for in vivo targeting in rats. These NPs released EDTA slowly for up to 5 days. In both ex-vivo study and in vivo study with injury-induced local abdominal aortic calcification, we showed that elastin antibody-coated and EDTA-loaded albumin NPs targeted the damaged elastic lamina while sparing healthy artery. Intravenous NP injections reversed elastin-specific MAC in rats after four injections over a 2-week period. EDTA-loaded albumin NPs did not cause the side effects observed in EDTA injection alone, such as decrease in serum calcium (Ca), increase in urine Ca, or toxicity to kidney. There was no bone loss in any treated groups. Conclusion We demonstrate that elastin antibody-coated and EDTA-loaded albumin NPs might be a promising nanoparticle therapy to reverse elastin-specific MAC and circumvent side effects associated with systemic EDTA chelation therapy. PMID:25285609

Targeted Drug Delivery in the Suprachoroidal Space by Swollen Hydrogel Pushing

PubMed Central

Jung, Jae Hwan; Desit, Patcharin; Prausnitz, Mark R.

2018-01-01

Purpose The purpose is to target model drug particles to the posterior region of the suprachoroidal space (SCS) of the eye controlled via pushing by hydrogel swelling. Methods A particle formulation containing 1% hyaluronic acid (HA) with fluorescent polymer particles and a hydrogel formulation containing 4% HA were introduced in a single syringe as two layers without mixing, and injected sequentially into the SCS of the rabbit eye ex vivo and in vivo using a microneedle. Distribution of particles in the eye was determined by microscopy. Results During injection, the particle formulation was pushed toward the middle of the SCS by the viscous hydrogel formulation, but less than 12% of particles reached the posterior SCS. After injection, the particle formulation was pushed further toward the macula and optic nerve in the posterior SCS by hydrogel swelling and spreading. Heating the eye to 37°C, or injecting in vivo decreased viscosity and mechanical strength of the hydrogel, thereby allowing it to swell and flow further in the SCS. A high salt concentration (9% NaCl) in the hydrogel formulation further increased hydrogel swelling due to osmotic flow into the hydrogel. In this way, up to 76% of particles were delivered to the posterior SCS from an injection made near the limbus. Conclusions This study shows that model drug particles can be targeted to the posterior SCS by HA hydrogel swelling and pushing without particle functionalization or administering external driving forces. PMID:29677369

Mu2e-II Injection from PIP-II

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neuffer, David

We discuss injection of 800 MeV proton beam from PIP-II into the production target for Mu2e-II, assuming a targeting and μ production scenario similar to mu2e. The incoming beam trajectory must be modified from the mu2e parameters to match the focusing fields. Adding a vertical deflection at injection enables the injected beam to reach the target. Other differences from the mu2e system must be considered, including changes in the target structure, the radiation shielding and beam dump/absorber. H- beam should be stripped to p+. Other variations are discussed.

‘On the same level’: facilitators’ experiences running a drug user-led safer injecting education campaign

PubMed Central

2013-01-01

Background Unsafe injection practices play a major role in elevated rates of morbidity and mortality among people who inject drugs (IDU). There is growing interest in the direct involvement of IDU in interventions that seek to address unsafe injecting. This study describes a drug user-led safer injecting education campaign, and explores facilitators’ experiences delivering educational workshops. Methods We conducted semi-structured qualitative interviews with 8 members of the Injection Support (IS) Team who developed and facilitated a series of safer injecting education workshops. Interviews explored facilitator’s perceptions of the workshops, experiences being a facilitator, and perspectives on the educational campaign. Interviews were transcribed verbatim and a thematic analysis was conducted. Results IS Team facilitators described how the workshop’s structure and content enabled effective communication of information about safer injecting practices, while targeting the unsafe practices of workshop participants. Facilitators’ identity as IDU enhanced their ability to relate to workshop participants and communicate educational messages in language accessible to workshop participants. Facilitators reported gaining knowledge and skills from their involvement in the campaign, as well as positive feelings about themselves from the realization that they were helping people to protect their health. Overall, facilitators felt that this campaign provided IDU with valuable information, although facilitators also critiqued the campaign and suggested improvements for future efforts. Conclusions This study demonstrates the feasibility of involving IDU in educational initiatives targeting unsafe injecting. Findings illustrate how IDU involvement in prevention activities improves relevance and cultural appropriateness of interventions while providing individual, social, and professional benefits to those IDU delivering education. PMID:23497293

Assessment of injection safety in Ha Dong General Hospital, Hanoi, in 2012

PubMed Central

Van Tuong, Phan; Phuong, Tran Thi Minh; Anh, Bui Thi My; Nguyen, Trang Huyen Thi

2017-01-01

Background: Injection is one of the most frequently used medical methods to introduce drugs or other substances into the body for purposes of treatment or prevention. Unsafe injection can cause adverse outcomes, such as abscess and anaphylactic shock, and increases the risk of blood-borne transmission of viruses to patients and health care workers, as well as the community. Recognizing the importance of injection safety, in 2000 the Vietnamese Ministry of Health (MOH) collaborated with the Vietnam Nurses Association to launch the “Safe injection” program throughout the country, including Hanoi. Methods: This cross-sectional study, combining quantitative and qualitative analysis, was conducted from February to August 2012 in Ha Dong General Hospital using a structured questionnaire and observation checklist. The target population of the study was 109 nurses working in clinical departments and 436 injections were observed. Results: The percentage of nurses who are familiar with injection safety standards was found to be 82.6%. The proportion of practical injections that met the 23 standards of injection safety set by the MOH amounted to 22.2%. The factors related to safe injection practice of nurses who were younger age group (OR=3.1; p<0.05) and fewer number of years working as a nurse (OR=2.8; p<0.05). Conclusions: While nurses have high level of knowledge about safe injections but a small proportion actually practiced. Experience may not always guarantee safe practices.  Injection safety training should be regularly imparted upon all categories of nurses. PMID:29188014

Pertinent anatomy and analysis for midface volumizing procedures.

PubMed

Surek, Christopher C; Beut, Javier; Stephens, Robert; Jelks, Glenn; Lamb, Jerome

2015-05-01

The study was conducted to construct an anatomically inspired midfacial analysis facilitating safe, accurate, and dynamic nonsurgical rejuvenation. Emphasis is placed on determining injection target areas and adverse event zones. Twelve hemifacial fresh cadavers were dissected in a layered fashion. Dimensional measurements between the midfacial fat compartments, prezygomatic space, mimetic muscles, and neurovascular bundles were used to develop a topographic analysis for clinical injections. A longitudinal line from the base of the alar crease to the medial edge of the levator anguli oris muscle (1.9 cm), lateral edge of the levator anguli oris muscle (2.6 cm), and zygomaticus major muscle (4.6 cm) partitions the cheek into two aesthetic regions. A six-step facial analysis outlines three target zones and two adverse event zones and triangulates the point of maximum cheek projection. The lower adverse event zone yields an anatomical explanation to inadvertent jowling during anterior cheek injection. The upper adverse event zone localizes the palpebral branch of the infraorbital artery. The medial malar target area isolates quadrants for anterior cheek projection and tear trough effacement. The middle malar target area addresses lid-cheek blending and superficial compartment turgor. The lateral malar target area highlights lateral cheek projection and locates the prezygomatic space. This stepwise analysis illustrates target areas and adverse event zones to achieve midfacial support, contour, and profile in the repose position and simultaneous molding of a natural shape during animation. This reproducible method can be used both procedurally and in record-keeping for midface volumizing procedures.

Validation and characterization of a novel method for selective vagal deafferentation of the gut.

PubMed

Diepenbroek, Charlene; Quinn, Danielle; Stephens, Ricky; Zollinger, Benjamin; Anderson, Seth; Pan, Annabelle; de Lartigue, Guillaume

2017-10-01

There is a lack of tools that selectively target vagal afferent neurons (VAN) innervating the gut. We use saporin (SAP), a potent neurotoxin, conjugated to the gastronintestinal (GI) hormone cholecystokinin (CCK-SAP) injected into the nodose ganglia (NG) of male Wistar rats to specifically ablate GI-VAN. We report that CCK-SAP ablates a subpopulation of VAN in culture. In vivo, CCK-SAP injection into the NG reduces VAN innervating the mucosal and muscular layers of the stomach and small intestine but not the colon, while leaving vagal efferent neurons intact. CCK-SAP abolishes feeding-induced c-Fos in the NTS, as well as satiation by CCK or glucagon like peptide-1 (GLP-1). CCK-SAP in the NG of mice also abolishes CCK-induced satiation. Therefore, we provide multiple lines of evidence that injection of CCK-SAP in NG is a novel selective vagal deafferentation technique of the upper GI tract that works in multiple vertebrate models. This method provides improved tissue specificity and superior separation of afferent and efferent signaling compared with vagotomy, capsaicin, and subdiaphragmatic deafferentation. NEW & NOTEWORTHY We develop a new method that allows targeted lesioning of vagal afferent neurons that innervate the upper GI tract while sparing vagal efferent neurons. This reliable approach provides superior tissue specificity and selectivity for vagal afferent over efferent targeting than traditional approaches. It can be used to address questions about the role of gut to brain signaling in physiological and pathophysiological conditions. Copyright © 2017 the American Physiological Society.

Isotope-dilution gas chromatography-mass spectrometry coupled with injection-port butylation for the determination of 4-t-octylphenol, 4-nonylphenols and bisphenol A in human urine.

PubMed

Chung, Shuang-Hung; Ding, Wang-Hsien

2018-02-05

An analytical method that utilizes isotope-dilution gas chromatography-mass spectrometry (ID-GC-MS) coupled with injection-port butylation was developed. The method was validated, and confirmed to be able to determine the presence of three commonly detected endocrine-disrupting chemicals (EDCs: 4-tert-octylphenol (4-t-OP), 4-nonylphenols (4-NPs) and bisphenol A (BPA)) in human urine with high precision and accuracy. After sample preparation by solid-phase extraction, the extract was introduced into GC-MS via injection-port butylation. The butylated target analytes were identified and quantified by using ion-trap mass spectrometry operating in the selected-ion-storage mode, and employing the measurement of peak area ratios of the butylated target analytes and labeled-analogues in the samples and calibration standards. The labeled-analogues were also used to correct the variations associated with the analysis and matrix effect. The limits of quantitation (LOQs) ranged from 0.1 to 0.3ng/mL. High precisions for both intra- and inter-day analysis ranged from 1 to 6%, and excellent accuracy (mean recovery) ranged from 92 to 105% on two concentration levels. In human urine, the total concentrations of three selected EDCs varied from 1.28 to 7.14ng/mL. 4-NPs were detected within all collected samples. The developed method allows accurate analysis of trace-level of EDCs in urine, and these target EDCs could act as useful biomarkers to assess exposure in biomonitoring studies and programs. Copyright © 2017 Elsevier B.V. All rights reserved.

Direct memory access transfer completion notification

DOEpatents

Chen, Dong; Giampapa, Mark E.; Heidelberger, Philip; Kumar, Sameer; Parker, Jeffrey J.; Steinmacher-Burow, Burkhard D.; Vranas, Pavlos

2010-07-27

Methods, compute nodes, and computer program products are provided for direct memory access (`DMA`) transfer completion notification. Embodiments include determining, by an origin DMA engine on an origin compute node, whether a data descriptor for an application message to be sent to a target compute node is currently in an injection first-in-first-out (`FIFO`) buffer in dependence upon a sequence number previously associated with the data descriptor, the total number of descriptors currently in the injection FIFO buffer, and the current sequence number for the newest data descriptor stored in the injection FIFO buffer; and notifying a processor core on the origin DMA engine that the message has been sent if the data descriptor for the message is not currently in the injection FIFO buffer.

Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study.

PubMed

Byrne, Elizabeth H; Anahtar, Melis N; Cohen, Kathleen E; Moodley, Amber; Padavattan, Nikita; Ismail, Nasreen; Bowman, Brittany A; Olson, Gregory S; Mabhula, Amanda; Leslie, Alasdair; Ndung'u, Thumbi; Walker, Bruce D; Ghebremichael, Musie S; Dong, Krista L; Kwon, Douglas S

2016-04-01

The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract. In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods. Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12·06 per 100 person-years, 95% CI 6·41-20·63) than women using no long-term contraception (3·71 per 100 person-years, 1·36-8·07; adjusted hazard ratio [aHR] 2·93, 95% CI 1·09-7·868, p=0·0326). HIV-negative injectable progestin-only contraceptive users had 3·92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0·0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3·25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0·0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives. Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure. The Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy.

PubMed

Galan, Alba; Barcelona, Pablo F; Nedev, Hinyu; Sarunic, Marinko V; Jian, Yifan; Saragovi, H Uri

2017-06-01

The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. We compared the pharmacokinetics of a single 40 μg subconjunctival (SCJ) depot to the reported effective 5 μg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.

Augmented Reality Visualization with Use of Image Overlay Technology for MR Imaging–guided Interventions: Assessment of Performance in Cadaveric Shoulder and Hip Arthrography at 1.5 T

PubMed Central

Fritz, Jan; U-Thainual, Paweena; Ungi, Tamas; Flammang, Aaron J.; Fichtinger, Gabor; Iordachita, Iulian I.

2012-01-01

Purpose: To prospectively assess overlay technology in providing accurate and efficient targeting for magnetic resonance (MR) imaging–guided shoulder and hip joint arthrography. Materials and Methods: A prototype augmented reality image overlay system was used in conjunction with a clinical 1.5-T MR imager. A total of 24 shoulder joint and 24 hip joint injections were planned in 12 human cadavers. Two operators (A and B) participated, each performing procedures on different cadavers using image overlay guidance. MR imaging was used to confirm needle positions, monitor injections, and perform MR arthrography. Accuracy was assessed according to the rate of needle adjustment, target error, and whether the injection was intraarticular. Efficiency was assessed according to arthrography procedural time. Operator differences were assessed with comparison of accuracy and procedure times between the operators. Mann-Whitney U test and Fisher exact test were used to assess group differences. Results: Forty-five arthrography procedures (23 shoulders, 22 hips) were performed. Three joints had prostheses and were excluded. Operator A performed 12 shoulder and 12 hip injections. Operator B performed 11 shoulder and 10 hip injections. Needle adjustment rate was 13% (six of 45; one for operator A and five for operator B). Target error was 3.1 mm ± 1.2 (standard deviation) (operator A, 2.9 mm ± 1.4; operator B, 3.5 mm ± 0.9). Intraarticular injection rate was 100% (45 of 45). The average arthrography time was 14 minutes (range, 6–27 minutes; 12 minutes [range, 6–25 minutes] for operator A and 16 minutes [range, 6–27 min] for operator B). Operator differences were not significant with regard to needle adjustment rate (P = .08), target error (P = .07), intraarticular injection rate (P > .99), and arthrography time (P = .22). Conclusion: Image overlay technology provides accurate and efficient MR guidance for successful shoulder and hip arthrography in human cadavers. © RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112640/-/DC1 PMID:22843764

Apparatus for producing laser targets

DOEpatents

Jarboe, T.R.; Baker, W.R.

1975-09-23

This patent relates to an apparatus and method for producing deuterium targets or pellets of 25u to 75u diameter. The pellets are sliced from a continuously spun solid deuterium thread at a rate of up to 10 pellets/second. The pellets after being sliced from the continuous thread of deuterium are collimated and directed to a point of use, such as a laser activated combustion or explosion chamber wherein the pellets are imploded by laser energy or laser produced target plasmas for neutral beam injection. (auth)

Ultra-low-dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model: How Little Can We See?

PubMed Central

Wang, Shiying; Herbst, Elizabeth B.; Mauldin, F. William; Diakova, Galina B.; Klibanov, Alexander L.; Hossack, John A.

2016-01-01

Objectives The objective of this study is to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model. Materials and Methods The pre-burst minus post-burst method was implemented on a Verasonics ultrasound research scanner using a multi-frame compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine, DSPC-based) microbubbles that were conjugated with anti-vascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts. Different injection doses ranging from 5 × 104 to 1 × 107 microbubbles per mouse were evaluated to determine the minimum diagnostically effective dose. Results The proposed imaging sequence was able to achieve statistically significant detection (p < 0.05, n = 5) of VEGFR2 in tumors with a minimum MBVEGFR2 injection dose of only 5 × 104 microbubbles per mouse (DSPC at 0.053 ng/g mouse body mass). Non-specific adhesion of MBControl at the same injection dose was negligible. Additionally, the targeted contrast ultrasound signal of MBVEGFR2 decreased with lower microbubble doses, while non-specific adhesion of MBControl increased with higher microbubble doses. Conclusions 5 × 104 microbubbles per animal is now the lowest injection dose on record for ultrasound molecular imaging to achieve statistically significant detection of molecular targets in vivo. Findings in this study provide us with further guidance for future developments of clinically translatable ultrasound molecular imaging applications using a lower dose of microbubbles. PMID:27654582

In Vivo Near-Infrared Imaging of Fibrin Deposition in Thromboembolic Stroke in Mice

PubMed Central

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Objectives Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa–targeted near-infrared fluorescence (NIRF) imaging. Materials and Methods The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. Results In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Conclusion Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke. PMID:22272319

Computed Tomography Demonstration of the Production and Distribution of Oxygen Gas Following Intratumoral Injection of a New Radiosensitizer (KORTUC) for Patients with Breast Cancer-Is Intratumoral Injection Not an Ideal Approach to Solve the Major Problem of Tumor Hypoxia in Radiotherapy?

PubMed

Hayashi, Naoya; Ogawa, Yasuhiro; Kubota, Kei; Okino, Kazuhiro; Akima, Ryo; Morita-Tokuhiro, Shiho; Tsuzuki, Akira; Yaogawa, Shin; Nishioka, Akihito; Miyamura, Mitsuhiko

2016-04-01

We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of -457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method.

Accuracy of MRI-compatible contrast media injectors.

PubMed

Saake, M; Wuest, W; Becker, S; Uder, M; Janka, R

2014-03-01

To analyze the exactness of MRI-compatible contrast media (CM) injectors in an experimental setup and clinical use. Ejected fluid volumes and amounts of CM were quantified for single and double piston injections. The focus was on small volumes, as used in pediatric examination and test-bolus measurements. Samples were collected before and after clinical MRI scans and amounts of CM were measured. For single piston injections the volume differences were minimal (mean difference 0.01  ml). For double piston injections the volume of the first injection was decreased (mean 20.74  ml, target 21.00  ml, p < 0.01). After a position change of the Y-piece of the injection system, the amount of CM differed significantly from the target value (mean 1.23  mmol and 0.83  mmol at 1  ml/s flow rate, target 1.00  mmol, p < 0.01), independently of the wait time. The clinical samples confirmed these findings. The pistons of modern CM injectors work exactly. However, for small CM volumes the injected amount of CM can differ significantly from the target value in both directions. Influence factors are an incomplete elimination of air and exchange processes between the CM and saline chaser in the injection system. • In MRI examinations of children and test-bolus measurements, small amounts of CM are used. • The accuracy of single piston injections is high. • In double piston injections the injected amount of CM can differ significantly from the target value. © Georg Thieme Verlag KG Stuttgart · New York.

Monitoring an EGS injection at Newberry Volcano using Magnetotelluric dimensionality analysis

NASA Astrophysics Data System (ADS)

Bowles-martinez, E.; Schultz, A.; Rose, K.; Urquhart, S.

2016-12-01

The sensitivity of magnetotelluric (MT) data to the presence of electrically conductive subsurface features makes it applicable for determining the extent of injected fluids in enhanced geothermal systems (EGS). We use MT to monitor fluid injection during tests of a proposed EGS site at Newberry Volcano in Central Oregon, USA. Newberry is a large shield volcano located where fault systems of the northern Basin and Range meet the Cascade Arc and the high lava plains. Its strong potential for geothermal energy has made it a target for energy exploration for over 40 years. MT measurements were made before, during, and after an EGS stimulation in 2014 in an effort to detect subsurface pathways taken by fluids that are attributable to stimulation. We begin by creating a baseline model from inverting over 200 wideband MT stations located in the western half of the volcano. This model is constrained by well logs, as well as by high resolution gravity and seismic velocity modeling. Our model shows conductive regions associated with the caldera's ring fault, likely showing where hydrothermal fluids or their mineral alteration products are present. However, as this is an EGS study, we are interested in detecting fluid intrusion into hot, dry rock. Therefore, our primary target is a resistive zone on the western flank of Newberry volcano that is interpreted as a series of hot intrusive sequences. Well bottom temperatures in this area have been measured in excess of 300 °C. The stimulation's effect on resistivity is subtle, in part because the injected fluid is fresh groundwater, the injected volume is modest, and the target depth is 2,000-3,000 m below ground level. We found that it is advantageous to look at the impedance tensor data directly to detect injected fluids. Because fluids and their associated change in resistivity are expected to be concentrated around the injection well, the injection will exhibit a highly three-dimensional resistivity structure. Therefore, we examine the impedance tensor for changes in dimensionality to mark the arrival of injected fluids. We then present a method of inverting MT data for changes in impedance rather than for resistivity.

A microinjection technique for targeting regions of embryonic and neonatal mouse brain in vivo

PubMed Central

Davidson, Steve; Truong, Hai; Nakagawa, Yasushi; Giesler, Glenn J

2009-01-01

A simple pressure injection technique was developed to deliver substances into specific regions of the embryonic and neonatal mouse brain in vivo. The retrograde tracers Fluorogold and cholera toxin B subunit were used to test the validity of the technique. Injected animals survived the duration of transport (24–48 hrs) and then were sacrificed and perfused with fixative. Small injections (≤ 50 nL) were contained within targeted structures of the perinatal brain and labeled distant cells of origin in several model neural pathways. Traced neural pathways in the perinatal mouse were further examined with immunohistochemical methods to test the feasibility of double labeling experiments during development. Several experimental situations in which this technique would be useful are discussed, for example, to label projection neurons in slice or culture preparations of mouse embryos and neonates. The administration of pharmacological or genetic vectors directly into specific neural targets during development should also be feasible. An examination of the form of neural pathways during early stages of life may lead to insights regarding the functional changes that occur during critical periods of development and provide an anatomic basis for some neurodevelopmental disorders. PMID:19840780

Evaluation of the 3-GeV proton beam profile at the spallation target of the JSNS

NASA Astrophysics Data System (ADS)

Meigo, Shin-ichiro; Noda, Fumiaki; Ishikura, Syuichi; Futakawa, Masatoshi; Sakamoto, Shinichi; Ikeda, Yujiro

2006-06-01

At JSNS, 3-GeV protons beam is delivered from rapid cycling synchrotron (RCS) to the spallation neutron target. In order to reduce the damage of pitting on the target container, the peak current density should be kept as small as possible. In this study, the beam profile at spallation neutron target is evaluated. The phase-space distribution, including the space-charge effect, is calculated with SIMPSONS code. The beam profile on the target is obtained with the transfer matrix from exit of RCS to the target. As for injection to RCS, two methods of correlated and anti-correlated painting are considered. By using anti-correlated painting for injection of beam at RCS, it is found the shape of beam becomes flatter than the distribution by using correlated painting. As other aspect for the study of target, in order to carry out target performance test especially for the study of pitting issue, it is better to have the beam profile variety from the beginning of facility. The adjustable range for the beam profile at the beginning is also studied. Although the beam shape is narrow and the duty is very low, the strong enough peak density is achievable equivalent as 1 MW.

Apparatus and method for preparing oxygen-15 labeled water H.sub.2 [.sup.15 O] in an injectable form for use in positron emission tomography

DOEpatents

Ferrieri, Richard A.; Schlyer, David J.; Alexoff, David

1996-01-09

A handling and processing apparatus for preparing Oxygen-15 labeled water (H.sub.2 [.sup.15 O]) in injectable form for use in Positron Emission Tomography from preferably H.sub.2 [.sup.15 O] produced by irradiating a flowing gas target of nitrogen and hydrogen. The apparatus includes a collector for receiving and directing a gas containing H.sub.2 [.sup.15 O] gas and impurities, mainly ammonia (NH.sub.3) gas into sterile water to trap the H.sub.2 [.sup.15 O] and form ammonium (NH.sub.4.sup.+) in the sterile water. A device for displacing the sterile water containing H.sub.2 [.sup.15 O] and NH.sub.4.sup.+ through a cation resin removes NH.sub.4.sup.+ from the sterile water. A device for combining the sterile water containing H.sub.2 [.sup.15 O] with a saline solution produces an injectable solution. Preferably, the apparatus includes a device for delivering the solution to a syringe for injection into a patient. Also, disclosed is a method for preparing H.sub.2 [.sup.15 O] in injectable form for use in Positron Emission Tomography in which the method neither requires isotopic exchange reaction nor application of high temperature.

Fabrication and evaluation of SDF-1 loaded galactosylated chitosan nanoparticles for liver targeting

NASA Astrophysics Data System (ADS)

Xue-Hui, Chu; Zhang-Qi, Feng; Qian, Xu; Jiang-Qiang, Xiao; Xian-Wen, Yuan; Xi-Tai, Sun

2017-03-01

Objective. SDF-1 loaded galactosylated chitosan (GC) nanoparticles for liver targeting were synthesized by electrospraying technique, and its biocompatibility and liver targeting effect were evaluated. Method. The SDF-1 loaded GC nanoparticles were constructed and its morphology was observed by the scanning electron microscopy (SEM). Hepatocytes were harvested and cocultured with the nanoparticles, and the albumin secretion and urea synthesis were detected by enzyme-linked immunosorbent assay assay, the concentration of lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) was also measured. Finally, the nanoparticles were injected intravenously through the caudal vein of rat, and its liver targeting effect was evaluated. Result. SEM showed the nanoparticles distributed uniformly, with an average diameter of 100 nm and a regular spherical shape. There was no significant difference in urea synthesis, albumin secretion, concentration of LDH and TNF-α between two groups (p > 0.05). The nanoparticles were significantly accumulated in the liver tissue after its injection, but seldom fluorescence signals were observed in the lung, spleen, heart and kidney. Conclusion. The SDF-1 loaded GC nanoparticles showed uniform distribution, good biocompatibility and liver targeting effect, and suggested its potential application as a liver targeting delivery system.

Validating An Analytic Completeness Model for Kepler Target Stars Based on Flux-level Transit Injection Experiments

NASA Astrophysics Data System (ADS)

Catanzarite, Joseph; Burke, Christopher J.; Li, Jie; Seader, Shawn; Haas, Michael R.; Batalha, Natalie; Henze, Christopher; Christiansen, Jessie; Kepler Project, NASA Advanced Supercomputing Division

2016-06-01

The Kepler Mission is developing an Analytic Completeness Model (ACM) to estimate detection completeness contours as a function of exoplanet radius and period for each target star. Accurate completeness contours are necessary for robust estimation of exoplanet occurrence rates.The main components of the ACM for a target star are: detection efficiency as a function of SNR, the window function (WF) and the one-sigma depth function (OSDF). (Ref. Burke et al. 2015). The WF captures the falloff in transit detection probability at long periods that is determined by the observation window (the duration over which the target star has been observed). The OSDF is the transit depth (in parts per million) that yields SNR of unity for the full transit train. It is a function of period, and accounts for the time-varying properties of the noise and for missing or deweighted data.We are performing flux-level transit injection (FLTI) experiments on selected Kepler target stars with the goal of refining and validating the ACM. “Flux-level” injection machinery inserts exoplanet transit signatures directly into the flux time series, as opposed to “pixel-level” injection, which inserts transit signatures into the individual pixels using the pixel response function. See Jie Li's poster: ID #2493668, "Flux-level transit injection experiments with the NASA Pleiades Supercomputer" for details, including performance statistics.Since FLTI is affordable for only a small subset of the Kepler targets, the ACM is designed to apply to most Kepler target stars. We validate this model using “deep” FLTI experiments, with ~500,000 injection realizations on each of a small number of targets and “shallow” FLTI experiments with ~2000 injection realizations on each of many targets. From the results of these experiments, we identify anomalous targets, model their behavior and refine the ACM accordingly.In this presentation, we discuss progress in validating and refining the ACM, and we compare our detection efficiency curves with those derived from the associated pixel-level transit injection experiments.Kepler was selected as the 10th mission of the Discovery Program. Funding for this mission is provided by NASA, Science Mission Directorate.

Effects of Sex Work on the Prevalence of Syphilis Among Injection Drug Users in 3 Russian Cities

PubMed Central

Platt, Lucy; Rhodes, Tim; Judd, Ali; Koshkina, Evgeniya; Maksimova, Svetlana; Latishevskaya, Natalia; Renton, Adrian; McDonald, Tamara; Parry, John V.

2007-01-01

Objectives. We examined risk factors for syphilis infection among injection drug users in 3 Russian Federation cities, focusing particular attention on the potential roles of gender and sex work. Methods. We conducted a cross-sectional survey of injection drug users in Moscow, Volgograd, and Barnaul, collecting behavioral data and testing for antibodies to Treponema pallidum. Associations between presence of antibodies to T pallidum and covariates were explored. Results. Overall, the prevalence of antibodies to T pallidum was 11% (95% confidence interval=9.7%, 13.1%). Syphilis was associated with involvement in sex work and with gender in Moscow and Barnaul but not in Volgograd. Female injection drug users not involved in sex work were more likely than men to be younger and to have recently begun to inject; female injection drug users involved in sex work were more likely than those not involved in sex work to inject daily. Conclusions. Syphilis transmission dynamics varied by region. Sex work can increase syphilis risk among injection drug users, potentially feeding the momentum of sexually transmitted HIV and syphilis among noninjectors. Targeted interventions are needed to reduce both sexual and injection risk behaviors among injection drug users. PMID:17018827

Targeting Apoptosis for Optical Imaging of Infection

PubMed Central

Thakur, Mathew L.; Zhang, Kaijun; Paudyal, Bishnuhari; Devakumar, Devadhas; Covarrubias, Maria Y.; Cheng, Changpo; Gray, Brian D.; Wickstrom, Eric; Pak, Koon Y.

2018-01-01

Purpose Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. Methods Bacterial infection and sterile inflammation were induced in separate groups (n=5) of mice. PS was targeted with a NIR fluorophore, PSVue®794 (2.7 pmol). Imaging was performed (ex=730 nm, em=830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. Results Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6±0.2) were greater than those in inflammation (3.2±0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. Conclusions Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection. PMID:21538153

Portable apparatus for separating sample and detecting target analytes

DOEpatents

Renzi, Ronald F.; Wally, Karl; Crocker, Robert W.; Stamps, James F.; Griffiths; Stewart K. ,; Fruetel, Julia A.; Horn, Brent A.; Shokair, Isaac R.; Yee, Daniel D.; VanderNoot, Victoria A.; Wiedenman, Boyd J.; West, Jason A. A.; Ferko, Scott M.

2008-11-18

Portable devices and methods for determining the presence of a target analyte using a portable device are provided. The portable device is preferably hand-held. A sample is injected to the portable device. A microfluidic separation is performed within the portable device and at least one separated component detected by a detection module within the portable device, in embodiments of the invention. A target analyte is identified, based on the separated component, and the presence of the target analyte is indicated on an output interface of the portable device, in accordance with embodiments of the invention.

Semi-automated solid phase extraction method for the mass spectrometric quantification of 12 specific metabolites of organophosphorus pesticides, synthetic pyrethroids, and select herbicides in human urine.

PubMed

Davis, Mark D; Wade, Erin L; Restrepo, Paula R; Roman-Esteva, William; Bravo, Roberto; Kuklenyik, Peter; Calafat, Antonia M

2013-06-15

Organophosphate and pyrethroid insecticides and phenoxyacetic acid herbicides represent important classes of pesticides applied in commercial and residential settings. Interest in assessing the extent of human exposure to these pesticides exists because of their widespread use and their potential adverse health effects. An analytical method for measuring 12 biomarkers of several of these pesticides in urine has been developed. The target analytes were extracted from one milliliter of urine by a semi-automated solid phase extraction technique, separated from each other and from other urinary biomolecules by reversed-phase high performance liquid chromatography, and detected using tandem mass spectrometry with isotope dilution quantitation. This method can be used to measure all the target analytes in one injection with similar repeatability and detection limits of previous methods which required more than one injection. Each step of the procedure was optimized to produce a robust, reproducible, accurate, precise and efficient method. The required selectivity and sensitivity for trace-level analysis (e.g., limits of detection below 0.5ng/mL) was achieved using a narrow diameter analytical column, higher than unit mass resolution for certain analytes, and stable isotope labeled internal standards. The method was applied to the analysis of 55 samples collected from adult anonymous donors with no known exposure to the target pesticides. This efficient and cost-effective method is adequate to handle the large number of samples required for national biomonitoring surveys. Published by Elsevier B.V.

Using well casing as an electrical source to monitor hydraulic fracture fluid injection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilt, Michael; Nieuwenhuis, Greg; MacLennan, Kris

2016-03-09

The depth to surface resistivity (DSR) method transmits current from a source located in a cased or openhole well to a distant surface return electrode while electric field measurements are made at the surface over the target of interest. This paper presents both numerical modelling results and measured data from a hydraulic fracturing field test where conductive water was injected into a resistive shale reservoir during a hydraulic fracturing operation. Modelling experiments show that anomalies due to hydraulic fracturing are small but measureable with highly sensitive sensor technology. The field measurements confirm the model results,showing that measured differences in themore » surface fields due to hydraulic fracturing have been detected above the noise floor. Our results show that the DSR method is sensitive to the injection of frac fluids; they are detectable above the noise floor in a commercially active hydraulic fracturing operation, and therefore this method can be used for monitoring fracture fluid movement.« less

Indocyanine Green Enables Near-Infrared Fluorescence Imaging of Lipid-Rich, Inflamed Atherosclerotic Plaques

PubMed Central

Vinegoni, Claudio; Botnaru, Ion; Aikawa, Elena; Calfon, Marcella A.; Iwamoto, Yoshiko; Folco, Eduardo J.; Ntziachristos, Vasilis; Weissleder, Ralph; Libby, Peter; Jaffer, Farouc A.

2011-01-01

New high-resolution molecular and structural imaging strategies are needed to visualize high-risk plaques that are likely to cause acute myocardial infarction, because current diagnostic methods do not reliably identify at-risk subjects. While molecular imaging agents are available for lower-resolution detection of atherosclerosis in large arteries, a lack of imaging agents coupled to high-resolution modalities has limited molecular imaging of atherosclerosis in the smaller coronary arteries [AU: ok? YES]. Here, we have demonstrated that indocyanine green (ICG), an FDA-approved near-infrared fluorescence (NIRF) emitting compound, targets atheromas within 20 minutes of injection and provides sufficient signal enhancement for in vivo detection of lipid-rich, inflamed, coronary-sized plaques in atherosclerotic rabbits. In vivo NIRF sensing was achieved with an intravascular wire in the aortae, a vessel of comparable caliber to human coronary arteries. Ex vivo fluorescence reflectance imaging studies showed high plaque target-to-background ratios in atheroma-bearing rabbits injected with ICG, compared to atheroma-bearing rabbits injected with saline. In vitro studies using human macrophages established that ICG preferentially targets lipid-loaded macrophages. In an early clinical study of human atheroma specimens from four patients, we found that ICG colocalized with plaque macrophages and lipids. The atheroma-targeting capability of ICG has the potential to accelerate the clinical development of NIRF molecular imaging of high-risk plaques in humans. PMID:21613624

Improved recovery demonstration for Williston Basin carbonates. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sippel, M.A.

The purpose of this project was to demonstrate targeted infill and extension drilling opportunities, better determinations of oil-in-place, and methods for improved completion efficiency. The investigations and demonstrations were focussed on Red River and Ratcliffe reservoirs in the Williston Basin within portions of Montana, North Dakota and South Dakota. Both of these formations have been successfully explored with conventional 2-dimensional (2D) seismic. Improved reservoir characterization utilizing 3-dimensional (3D) seismic was investigated for identification of structural and stratigraphic reservoir compartments. These seismic characterizations were integrated with geological and engineering studies. The project tested lateral completion techniques, including high-pressure jetting lance technologymore » and short-radius lateral drilling to enhance completion efficiency. Lateral completions should improve economics for both primary and secondary oil where low permeability is a problem and higher-density drilling of vertical infill wells is limited by drilling cost. New vertical wells were drilled to test bypassed oil in ares that were identified by 3D seismic. These new wells are expected to recover as much or greater oil than was produced by nearby old wells. The project tested water injection through vertical and horizontal wells in reservoirs where application of waterflooding has been limited. A horizontal well was drilled for testing water injection. Injection rates were tested at three times that of a vertical well. This demonstration well shows that water injection with horizontal completions can improve injection rates for economic waterflooding. This report is divided into two sections, part 1 covers the Red River and part 2 covers the Ratcliffe. Each part summarizes integrated reservoir characterizations and outlines methods for targeting by-passed oil reserves in the respective formation and locality.« less

A novel technique based on in vitro oocyte injection to improve CRISPR/Cas9 gene editing in zebrafish

PubMed Central

Xie, Shao-Lin; Bian, Wan-Ping; Wang, Chao; Junaid, Muhammad; Zou, Ji-Xing; Pei, De-Sheng

2016-01-01

Contemporary improvements in the type II clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system offer a convenient way for genome editing in zebrafish. However, the low efficiencies of genome editing and germline transmission require a time-intensive and laborious screening work. Here, we reported a method based on in vitro oocyte storage by injecting oocytes in advance and incubating them in oocyte storage medium to significantly improve the efficiencies of genome editing and germline transmission by in vitro fertilization (IVF) in zebrafish. Compared to conventional methods, the prior micro-injection of zebrafish oocytes improved the efficiency of genome editing, especially for the sgRNAs with low targeting efficiency. Due to high throughputs, simplicity and flexible design, this novel strategy will provide an efficient alternative to increase the speed of generating heritable mutants in zebrafish by using CRISPR/Cas9 system. PMID:27680290

Hierarchical Simulation to Assess Hardware and Software Dependability

NASA Technical Reports Server (NTRS)

Ries, Gregory Lawrence

1997-01-01

This thesis presents a method for conducting hierarchical simulations to assess system hardware and software dependability. The method is intended to model embedded microprocessor systems. A key contribution of the thesis is the idea of using fault dictionaries to propagate fault effects upward from the level of abstraction where a fault model is assumed to the system level where the ultimate impact of the fault is observed. A second important contribution is the analysis of the software behavior under faults as well as the hardware behavior. The simulation method is demonstrated and validated in four case studies analyzing Myrinet, a commercial, high-speed networking system. One key result from the case studies shows that the simulation method predicts the same fault impact 87.5% of the time as is obtained by similar fault injections into a real Myrinet system. Reasons for the remaining discrepancy are examined in the thesis. A second key result shows the reduction in the number of simulations needed due to the fault dictionary method. In one case study, 500 faults were injected at the chip level, but only 255 propagated to the system level. Of these 255 faults, 110 shared identical fault dictionary entries at the system level and so did not need to be resimulated. The necessary number of system-level simulations was therefore reduced from 500 to 145. Finally, the case studies show how the simulation method can be used to improve the dependability of the target system. The simulation analysis was used to add recovery to the target software for the most common fault propagation mechanisms that would cause the software to hang. After the modification, the number of hangs was reduced by 60% for fault injections into the real system.

Anatomical Regional Targeted (ART) BOTOX Injection Technique: A Novel Paradigm for Migraines and Chronic Headaches

PubMed Central

Sanniec, Kyle; Pezeshk, Ronnie; Chung, Michael

2016-01-01

Summary: Migraine headaches are a debilitating disease that causes significant socioeconomic problems. One of the speculated etiologies of the generation of migraines is peripheral nerve irritation at different trigger points. The use of Onabotulinum toxin A (BOTOX), although initially a novel approach, has now been determined to be a valid treatment for chronic headaches and migraines as described in the Phase III Research Evaluating Migraine Prophylaxis Therapy trials that prompted the approval by the Food and Drug Administration for treatment of chronic migraines. The injection paradigm established by this trial was one of a broad injection pattern across large muscle groups that did not always correspond to the anatomical locations of nerves. The senior author developed the Anatomical Regional Targeted BOTOX injection paradigm as an alternative to the current injection model. This technique targets both the anatomical location of nerves known to have causal effects with migraines and the region where the pain localizes, to provide relief across a wide distribution of the peripheral nerve. This article serves as a guide to the Anatomical Regional Targeted injection technique, which, to our knowledge, is the first comprehensive BOTOX injection paradigm described in the literature for treatment of migraines that targets nerves and nerve areas rather than purely muscle groups. This technique is based on the most up-to-date anatomical and scientific studies and large-volume migraine surgery experience. PMID:28293532

Modulating drug resistance by targeting BCRP/ABCG2 using retrovirus-mediated RNA interference.

PubMed

Xie, Ni; Mou, Lisha; Yuan, Jianhui; Liu, Wenlan; Deng, Tingting; Li, Zigang; Jing, Yi; Jin, Yi; Hu, Zhangli

2014-01-01

The BCRP/ABCG2 transporter, which mediates drug resistance in many types of cells, depends on energy provided by ATP hydrolysis. Here, a retrovirus encoding a shRNA targeting the ATP-binding domain of this protein was used to screen for highly efficient agents that could reverse drug resistance and improve cell sensitivity to drugs, thus laying the foundation for further studies and applications. To target the ATP-binding domain of BCRP/ABCG2, pLenti6/BCRPsi shRNA recombinant retroviruses, with 20 bp target sequences starting from the 270th, 745th and 939th bps of the 6th exon, were constructed and packaged. The pLenti6/BCRPsi retroviruses (V-BCRPi) that conferred significant knockdown effects were screened using a drug-sensitivity experiment and flow cytometry. The human choriocarcinoma cell line JAR, which highly expresses endogenous BCRP/ABCG2, was injected under the dorsal skin of a hairless mouse to initiate a JAR cytoma. After injecting V-BCRPi-infected JAR tumor cells into the dorsal skin of hairless mice, BCRP/ABCG2 expression in the tumor tissue was determined using immunohistochemistry, fluorescent quantitative RT-PCR and Western blot analyses. After intraperitoneal injection of BCRP/ABCG2-tolerant 5-FU, the tumor volume, weight change, and apoptosis rate of the tumor tissue were determined using in situ hybridization. V-BCRPi increased the sensitivity of the tumor histiocytes to 5-FU and improved the cell apoptosis-promoting effects of 5-FU in the tumor. The goal of the in vivo and in vitro studies was to screen for an RNA interference recombinant retrovirus capable of stably targeting the ATP-binding domain of BCRP/ABCG2 (V-BCRPi) to inhibit its function. A new method to improve the chemo-sensitivity of breast cancer and other tumor cells was discovered, and this method could be used for gene therapy and functional studies of malignant tumors.

Arthritis imaging using a near-infrared fluorescence folate-targeted probe

PubMed Central

Chen, Wei-Tsung; Mahmood, Umar; Weissleder, Ralph; Tung, Ching-Hsuan

2005-01-01

A recently developed near-infrared fluorescence-labeled folate probe (NIR2-folate) was tested for in vivo imaging of arthritis using a lipopolysaccharide intra-articular injection model and a KRN transgenic mice serum induction mouse model. In the lipopolysaccharide injection model, the fluorescence signal intensity of NIR2-folate (n = 12) and of free NIR2 (n = 5) was compared between lipopolysaccharide-treated and control joints. The fluorescence signal intensity of the NIR2-folate probe at the inflammatory joints was found to be significantly higher than the control normal joints (up to 2.3-fold, P < 0.001). The NIR2-free dye injection group showed a persistent lower enhancement ratio than the NIR2-folate probe injection group. Excessive folic acid was also given to demonstrate a competitive effect with the NIR2-folate. In the KRN serum transfer model (n = 4), NIR2-folate was applied at different time points after serum transfer, and the inflamed joints could be detected as early as 30 hours after arthritogenic antibody transfer (1.8-fold increase in signal intensity). Fluorescence microscopy, histology, and immunohistochemistry validated the optical imaging results. We conclude that in vivo arthritis detection was feasible using a folate-targeted near-infrared fluorescence probe. This receptor-targeted imaging method may facilitate improved arthritis diagnosis and early assessment of the disease progress by providing an in vivo characterization of active macrophage status in inflammatory joint diseases. PMID:15743478

Protein Drug Targets of Lavandula angustifolia on treatment of Rat Alzheimer's Disease

PubMed Central

Zali, Hakimeh; Zamanian-Azodi, Mona; Rezaei Tavirani, Mostafa; Akbar-zadeh Baghban, Alireza

2015-01-01

Different treatment strategies of Alzheimer's disease (AD) are being studied for treating or slowing the progression of AD. Many pharmaceutically important regulation systems operate through proteins as drug targets. Here, we investigate the drug target proteins in beta-amyloid (Aβ) injected rat hippocampus treated with Lavandula angustifolia (LA) by proteomics techniques. The reported study showed that lavender extract (LE) improves the spatial performance in AD animal model by diminishing Aβ production in histopathology of hippocampus, so in this study neuroprotective proteins expressed in Aβ injected rats treated with LE were scrutinized. Rats were divided into three groups including normal, Aβ injected, and Aβ injected that was treated with LE. Protein expression profiles of hippocampus tissue were determined by two-dimensional electrophoresis (2DE) method and dysregulated proteins such as Snca, NF-L, Hspa5, Prdx2, Apoa1, and Atp5a1were identified by MALDI-TOF/TOF. KEGG pathway and gene ontology (GO) categories were used by searching DAVID Bioinformatics Resources. All detected protein spots were used to determine predictedinteractions with other proteins in STRING online database. Different isoforms of important protein, Snca that exhibited neuroprotective effects by anti-apoptotic properties were expressed. NF-L involved in the maintenance of neuronal caliber. Hspa5 likewise Prdx2 displays as anti-apoptotic protein that Prdx2 also involved in the neurotrophic effects. Apoa1 has anti-inflammatory activity and Atp5a1, produces ATP from ADP. To sum up, these proteins as potential drug targets were expressed in hippocampus in response to effective components in LA may have therapeutic properties for the treatment of AD and other neurodegenerative diseases. PMID:25561935

Optimization of a Clinically Relevant Model of White Matter Stroke in Mice: Histological and Functional Evidences

PubMed Central

Ahmad, Abdullah S.; Satriotomo, Irawan; Fazal, Jawad A.; Nadeau, Stephen E.; Doré, Sylvain

2015-01-01

Background and Purpose White matter (WM) injury during stroke increases the risk of disability and gloomy prognosis of post-stroke rehabilitation. However, modeling of WM loss in rodents has proven to be challenging. Methods We report improved WM injury models in male C57BL/6 mice. Mice were given either endothelin-1 (ET-1) or L-N5-(1-iminoethyl)ornitine (L-NIO) into the periventricular white matter (PVWM), in the corpus callosum (CC), or in the posterior limb of internal capsule (PLIC). Anatomical and functional outcomes were quantified on day 7 post injection. Results Injection of ET-1 or L-NIO caused a small focal lesion in the injection site in the PVWM. No significant motor function deficits were observed in the PVWM lesion model. We next targeted the PLIC by using single or double injections of L-NIO and found that this strategy induced small focal infarction. Interestingly, injection of L-NIO in the PLIC also resulted in gliosis, and significant motor function deficits. Conclusions By employing different agents, doses, and locations, this study shows the feasibility of inducing brain WM injury accompanied with functional deficits in mice. Selective targeting of the injury location, behavioral testing, and the agents chosen to induce WM injury are all keys to successfully develop a mouse model and subsequent testing of therapeutic interventions against WM injury. PMID:27512724

Fuel governor for controlled autoignition engines

DOEpatents

Jade, Shyam; Hellstrom, Erik; Stefanopoulou, Anna; Jiang, Li

2016-06-28

Methods and systems for controlling combustion performance of an engine are provided. A desired fuel quantity for a first combustion cycle is determined. One or more engine actuator settings are identified that would be required during a subsequent combustion cycle to cause the engine to approach a target combustion phasing. If the identified actuator settings are within a defined acceptable operating range, the desired fuel quantity is injected during the first combustion cycle. If not, an attenuated fuel quantity is determined and the attenuated fuel quantity is injected during the first combustion cycle.

Two-parameter monitoring in a lab-on-valve manifold, applied to intracellular H2O2 measurements.

PubMed

Lähdesmäki, Ilkka; Chocholous, Petr; Carroll, Andrea D; Anderson, Judy; Rabinovitch, Peter S; Ruzicka, Jaromir

2009-07-01

This work introduces, for the first time, simultaneous monitoring of fluorescence and absorbance using Bead Injection in a Lab-on-valve format. The aim of the paper is to show that when the target species, cells immobilized on a stationary phase, are exposed to reagents under well-controlled reaction conditions, dual monitoring yields valuable information. The applicability of this technique is demonstrated by the development of a Bead Injection method for automated measurement of cell density and intracellular hydrogen peroxide.

Evaluation of a Thermoprotective Gel for Hydrodissection During Percutaneous Microwave Ablation: In Vivo Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moreland, Anna J., E-mail: ajmoreland@gmail.com; Lubner, Meghan G., E-mail: mlubner@uwhealth.org; Ziemlewicz, Timothy J., E-mail: tziemlewicz@uwhealth.org

2015-06-15

PurposeTo evaluate whether thermoreversible poloxamer 407 15.4 % in water (P407) can protect non-target tissues adjacent to microwave (MW) ablation zones in a porcine model.Materials and MethodsMW ablation antennas were placed percutaneously into peripheral liver, spleen, or kidney (target tissues) under US and CT guidance in five swine such that the expected ablation zones would extend into adjacent diaphragm, body wall, or bowel (non-target tissues). For experimental ablations, P407 (a hydrogel that transitions from liquid at room temperature to semi-solid at body temperature) was injected into the potential space between target and non-target tissues, and the presence of a gel barriermore » was verified on CT. No barrier was used for controls. MW ablation was performed at 65 W for 5 min. Thermal damage to target and non-target tissues was evaluated at dissection.ResultsAntennas were placed 7 ± 3 mm from the organ surface for both control and gel-protected ablations (p = 0.95). The volume of gel deployed was 49 ± 27 mL, resulting in a barrier thickness of 0.8 ± 0.5 cm. Ablations extended into non-target tissues in 12/14 control ablations (mean surface area = 3.8 cm{sup 2}) but only 4/14 gel-protected ablations (mean surface area = 0.2 cm{sup 2}; p = 0.0005). The gel barrier remained stable at the injection site throughout power delivery.ConclusionWhen used as a hydrodissection material, P407 protected non-targeted tissues and was successfully maintained at the injection site for the duration of power application. Continued investigations to aid clinical translation appear warranted.« less

Topics in LIFE Target Survival: 11-SI-004 Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miles, Robin; Benett, Bill; Bond, Tiziana

The LIFE target design incorporates many considerations to generate the desired fusion gain including the physics design, the cost of manufacturing of the target, the injectability of the target, the aerodynamic flight characteristics of the target, the ability to track and engage the target and to maintain the structural and thermal integrity of the target. This document describes the effort that was made in support of issues of survivability of the target during injection which included issues massmanufactural materials and processes which could be used in the target.

Quantitative ultrasound molecular imaging by modeling the binding kinetics of targeted contrast agent

NASA Astrophysics Data System (ADS)

Turco, Simona; Tardy, Isabelle; Frinking, Peter; Wijkstra, Hessel; Mischi, Massimo

2017-03-01

Ultrasound molecular imaging (USMI) is an emerging technique to monitor diseases at the molecular level by the use of novel targeted ultrasound contrast agents (tUCA). These consist of microbubbles functionalized with targeting ligands with high-affinity for molecular markers of specific disease processes, such as cancer-related angiogenesis. Among the molecular markers of angiogenesis, the vascular endothelial growth factor receptor 2 (VEGFR2) is recognized to play a major role. In response, the clinical-grade tUCA BR55 was recently developed, consisting of VEGFR2-targeting microbubbles which can flow through the entire circulation and accumulate where VEGFR2 is over-expressed, thus causing selective enhancement in areas of active angiogenesis. Discrimination between bound and free microbubbles is crucial to assess cancer angiogenesis. Currently, this is done non-quantitatively by looking at the late enhancement, about 10 min after injection, or by calculation of the differential targeted enhancement, requiring the application of a high-pressure ultrasound (US) burst to destroy all the microbubbles in the acoustic field and isolate the signal coming only from bound microbubbles. In this work, we propose a novel method based on mathematical modeling of the binding kinetics during the tUCA first pass, thus reducing the acquisition time and with no need for a destructive US burst. Fitting time-intensity curves measured with USMI by the proposed model enables the assessment of cancer angiogenesis at both the vascular and molecular levels. This is achieved by estimation of quantitative parameters related to the microvascular architecture and microbubble binding. The proposed method was tested in 11 prostate-tumor bearing rats by performing USMI after injection of BR55, and showed good agreement with current USMI methods. The novel information provided by the proposed method, possibly combined with the current non-quantitative methods, may bring deeper insight into cancer angiogenesis, and thus potentially improve cancer diagnosis and management.

Challenges Surrounding the Injection and Arrival of Targets at LIFE Fusion Chamber Center

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miles, R; Spaeth, M; Manes, K

2010-12-01

IFE target designers must consider several engineering requirements in addition to the physics requirements for successful target implosion. These considerations include low target cost, high manufacturing throughput, the ability of the target to survive the injection into the fusion chamber and arrive in a condition and physical position consistent with proper laser-target interaction and ease of post-implosion debris removal. This article briefly describes these considerations for the Laser Inertial Fusion-based Energy (LIFE) targets currently being designed.

Designing optimal stimuli to control neuronal spike timing

PubMed Central

Packer, Adam M.; Yuste, Rafael; Paninski, Liam

2011-01-01

Recent advances in experimental stimulation methods have raised the following important computational question: how can we choose a stimulus that will drive a neuron to output a target spike train with optimal precision, given physiological constraints? Here we adopt an approach based on models that describe how a stimulating agent (such as an injected electrical current or a laser light interacting with caged neurotransmitters or photosensitive ion channels) affects the spiking activity of neurons. Based on these models, we solve the reverse problem of finding the best time-dependent modulation of the input, subject to hardware limitations as well as physiologically inspired safety measures, that causes the neuron to emit a spike train that with highest probability will be close to a target spike train. We adopt fast convex constrained optimization methods to solve this problem. Our methods can potentially be implemented in real time and may also be generalized to the case of many cells, suitable for neural prosthesis applications. With the use of biologically sensible parameters and constraints, our method finds stimulation patterns that generate very precise spike trains in simulated experiments. We also tested the intracellular current injection method on pyramidal cells in mouse cortical slices, quantifying the dependence of spiking reliability and timing precision on constraints imposed on the applied currents. PMID:21511704

Engineered Lentivector Targeting of Dendritic Cells for In Vivo Immunization

PubMed Central

Yang, Lili; Yang, Haiguang; Rideout, Kendra; Cho, Taehoon; Joo, Kye il; Ziegler, Leslie; Elliot, Abigail; Walls, Anthony; Yu, Dongzi; Baltimore, David; Wang, Pin

2008-01-01

We report a method of inducing antigen production in dendritic cells (DCs) by in vivo targeting with lentiviral vectors that specifically bind to the DC surface protein, DC-SIGN. To target the DCs, the lentivector was enveloped with a viral glycoprotein from Sindbis virus, engineered to be DC-SIGN-specific. In vitro, this lentivector specifically transduced DCs and induced DC maturation. A remarkable frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks following injection of a targeted lentiviral vector encoding an OVA transgene into naïve mice. These mice were solidly protected against the growth of the OVA-expressing E.G7 tumor and this methodology could even induce regression of an established tumor. Thus, lentiviral vectors targeting DCs provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens. PMID:18297056

Interpreting comprehensive two-dimensional gas chromatography using peak topography maps with application to petroleum forensics.

PubMed

Ghasemi Damavandi, Hamidreza; Sen Gupta, Ananya; Nelson, Robert K; Reddy, Christopher M

2016-01-01

Comprehensive two-dimensional gas chromatography [Formula: see text] provides high-resolution separations across hundreds of compounds in a complex mixture, thus unlocking unprecedented information for intricate quantitative interpretation. We exploit this compound diversity across the [Formula: see text] topography to provide quantitative compound-cognizant interpretation beyond target compound analysis with petroleum forensics as a practical application. We focus on the [Formula: see text] topography of biomarker hydrocarbons, hopanes and steranes, as they are generally recalcitrant to weathering. We introduce peak topography maps (PTM) and topography partitioning techniques that consider a notably broader and more diverse range of target and non-target biomarker compounds compared to traditional approaches that consider approximately 20 biomarker ratios. Specifically, we consider a range of 33-154 target and non-target biomarkers with highest-to-lowest peak ratio within an injection ranging from 4.86 to 19.6 (precise numbers depend on biomarker diversity of individual injections). We also provide a robust quantitative measure for directly determining "match" between samples, without necessitating training data sets. We validate our methods across 34 [Formula: see text] injections from a diverse portfolio of petroleum sources, and provide quantitative comparison of performance against established statistical methods such as principal components analysis (PCA). Our data set includes a wide range of samples collected following the 2010 Deepwater Horizon disaster that released approximately 160 million gallons of crude oil from the Macondo well (MW). Samples that were clearly collected following this disaster exhibit statistically significant match [Formula: see text] using PTM-based interpretation against other closely related sources. PTM-based interpretation also provides higher differentiation between closely correlated but distinct sources than obtained using PCA-based statistical comparisons. In addition to results based on this experimental field data, we also provide extentive perturbation analysis of the PTM method over numerical simulations that introduce random variability of peak locations over the [Formula: see text] biomarker ROI image of the MW pre-spill sample (sample [Formula: see text] in Additional file 4: Table S1). We compare the robustness of the cross-PTM score against peak location variability in both dimensions and compare the results against PCA analysis over the same set of simulated images. Detailed description of the simulation experiment and discussion of results are provided in Additional file 1: Section S8. We provide a peak-cognizant informational framework for quantitative interpretation of [Formula: see text] topography. Proposed topographic analysis enables [Formula: see text] forensic interpretation across target petroleum biomarkers, while including the nuances of lesser-known non-target biomarkers clustered around the target peaks. This allows potential discovery of hitherto unknown connections between target and non-target biomarkers.

Tumor radioimmunoimaging of chimeric antibody in nude mice with hepatoma xenograft

PubMed Central

Gong, Yi; Liu, Kang-Da; Zhou, Ge; Xue, Qiong; Chen, Shao-Liang; Tang, Zhao-You

1998-01-01

AIM: To study the radioimmunoimaging (RAII) using the human/mouse chimeric Ab to evaluate its targeting activity in animal models. METHODS: To chimeric Ab was labeled with 131I. RAII was performed at different intervals after injection of radio-labeled Abs in nude mice with human hepatoma xenograft, and tissue distribution of radioactivity was measured. Comparison was made in the chimeric Ab between the single segment Ab and previous murine mAb against HBxAg. RESULTS: The experimental objects developed tumor-positive image after 2 days of radio-labeled Abs injection, and the peak accumulation of radioactivity fell on the 7th day. The tumor/liver ratioactivity of the chimeric Ab, single segment Ab, anti-HBx mAb, and the control group was 281 ± 0.21, 2.44 ± 0.16, 4.60 ± 0.19, and 0.96 ± 0.14, respectively. CONCLUSION: The genetic engineering Abs have a considerable targeting activity which can be used as a novel humanized vector in the targeting treatment of liver cancer. PMID:11819217

Apparatus and method for preparing oxygen-15 labeled water H{sub 2}[{sup 15}O] in an injectable form for use in positron emission tomography

DOEpatents

Ferrieri, R.A.; Schlyer, D.J.; Alexoff, D.

1996-01-09

A handling and processing apparatus is revealed for preparing Oxygen-15 labeled water (H{sub 2}[{sup 15}O]) in injectable form for use in Positron Emission Tomography from preferably H{sub 2}[{sup 15}O] produced by irradiating a flowing gas target of nitrogen and hydrogen. The apparatus includes a collector for receiving and directing a gas containing H{sub 2}[{sup 15}O] gas and impurities, mainly ammonia (NH{sub 3}) gas into sterile water to trap the H{sub 2}[{sup 15}O] and form ammonium (NH{sub 4}{sup +}) in the sterile water. A device for displacing the sterile water containing H{sub 2}[{sup 15}O] and NH{sub 4}{sup +} through a cation resin removes NH{sub 4}{sup +} from the sterile water. A device for combining the sterile water containing H{sub 2}[{sup 15}O] with a saline solution produces an injectable solution. Preferably, the apparatus includes a device for delivering the solution to a syringe for injection into a patient. Also, disclosed is a method for preparing H{sub 2}[{sup 15}O] in injectable form for use in Positron Emission Tomography in which the method neither requires isotopic exchange reaction nor application of high temperature. 7 figs.

[Developing traditional Chinese medicine injection is the need for curing sickness to save patients].

PubMed

He, Ping; Li, Feng-Jie; Li, Lian-da; Li, Yi-Kui

2017-03-01

Safety issues of traditional Chinese medicine injections has been heated debate. There are two diametrically opposed views: it should be used reasonable and developed healthily or be forbidden to use. Some people have many misunderstandings and prejudices about the safety of traditional Chinese medicine injections. Compared with western medicine,traditional Chinese medicine has its own particularity. Traditional Chinese medicine has complex components. Its research and clinical application is different from western medicine. Adverse reactions of traditional Chinese medicine injections are related to many factors,such as a large number of irrational use,blind use of traditional Chinese medicine injections and western medicine injections,counterfeit and substandard drugs,incorrect methods of intravenous infusion,toxicity of supplementary materials,drug ingredients. Developing traditional Chinese medicine injection is the need for curing sickness to save patients. The purposeful, targeted, organized and planned systematic research of traditional Chinese medicine injections should be strengthened,especially the safety of traditional Chinese medicine. Strengthen supervision and control of rational drug use.Strengthen the examination and approval,supervision and management of all aspects to ensure the safety of patients. Copyright© by the Chinese Pharmaceutical Association.

Electron linac for medical isotope production with improved energy efficiency and isotope recovery

DOEpatents

Noonan, John; Walters, Dean; Virgo, Matt; Lewellen, John

2015-09-08

A method and isotope linac system are provided for producing radio-isotopes and for recovering isotopes. The isotope linac is an energy recovery linac (ERL) with an electron beam being transmitted through an isotope-producing target. The electron beam energy is recollected and re-injected into an accelerating structure. The ERL provides improved efficiency with reduced power requirements and provides improved thermal management of an isotope target and an electron-to-x-ray converter.

Kepler Planet Detection Metrics: Per-Target Flux-Level Transit Injection Tests of TPS for Data Release 25

NASA Technical Reports Server (NTRS)

Burke, Christopher J.; Catanzarite, Joseph

2017-01-01

Quantifying the ability of a transiting planet survey to recover transit signals has commonly been accomplished through Monte-Carlo injection of transit signals into the observed data and subsequent running of the signal search algorithm (Gilliland et al., 2000; Weldrake et al., 2005; Burke et al., 2006). In order to characterize the performance of the Kepler pipeline (Twicken et al., 2016; Jenkins et al., 2017) on a sample of over 200,000 stars, two complementary injection and recovery tests are utilized:1. Injection of a single transit signal per target into the image or pixel-level data, hereafter referred to as pixel-level transit injection (PLTI), with subsequent processing through the Photometric Analysis (PA), Presearch Data Conditioning (PDC), Transiting Planet Search (TPS), and Data Validation (DV) modules of the Kepler pipeline. The PLTI quantification of the Kepler pipeline's completeness has been described previously by Christiansen et al. (2015, 2016); the completeness of the final SOC 9.3 Kepler pipeline acting on the Data Release 25 (DR25) light curves is described by Christiansen (2017).2. Injection of multiple transit signals per target into the normalized flux time series data with a subsequent transit search using a stream-lined version of the Transiting Planet Search (TPS) module. This test, hereafter referred to as flux-level transit injection (FLTI), is the subject of this document. By running a heavily modified version of TPS, FLTI is able to perform many injections on selected targets and determine in some detail which injected signals are recoverable. Significant numerical efficiency gains are enabled by precomputing the data conditioning steps at the onset of TPS and limiting the search parameter space (i.e., orbital period, transit duration, and ephemeris zero-point) to a small region around each injected transit signal.The PLTI test has the advantage that it follows transit signals through all processing steps of the Kepler pipeline, and the recovered signals can be further classified as planet candidates or false positives in the exact same manner as detections from the nominal (i.e., observed) pipeline run (Twicken et al., 2016, Thompson et al., in preparation). To date, the PLTI test has been the standard means of measuring pipeline completeness averaged over large samples of targets (Christiansen et al., 2015, 2016; Christiansen, 2017). However, since the PLTI test uses only one injection per target, it does not elucidate individual-target variations in pipeline completeness due to differences in stellar properties or astrophysical variability. Thus, we developed the FLTI test to provide a numerically efficient way to fully map individual targets and explore the performance of the pipeline in greater detail. The FLTI tests thereby allow a thorough validation of the pipeline completeness models (such as window function (Burke and Catanzarite, 2017a), detection efficiency (Burke Catanzarite, 2017b), etc.) across the spectrum of Kepler targets (i.e., various astrophysical phenomena and differences in instrumental noise). Tests during development of the FLTI capability revealed that there are significant target-to-target variations in the detection efficiency.

Intradermal injection of an anti-Langerin-HIVGag fusion vaccine targets epidermal Langerhans cells in nonhuman primates and can be tracked in vivo.

PubMed

Salabert, Nina; Todorova, Biliana; Martinon, Frédéric; Boisgard, Raphaël; Zurawski, Gerard; Zurawski, Sandra; Dereuddre-Bosquet, Nathalie; Cosma, Antonio; Kortulewski, Thierry; Banchereau, Jacques; Levy, Yves; Le Grand, Roger; Chapon, Catherine

2016-03-01

The development of new immunization strategies requires a better understanding of early molecular and cellular events occurring at the site of injection. The skin is particularly rich in immune cells and represents an attractive site for vaccine administration. Here, we specifically targeted vaccine antigens to epidermal Langerhans cells (LCs) using a fusion protein composed of HIV antigens and a monoclonal antibody targeting Langerin. We developed a fluorescence imaging approach to visualize, in vivo, the vaccine-targeted cells. Studies were performed in nonhuman primates (NHPs) because of their relevance as a model to assess human vaccines. We directly demonstrated that in NHPs, intradermally injected anti-Langerin-HIVGag specifically targets epidermal LCs and induces rapid changes in the LC network, including LC activation and migration out of the epidermis. Vaccine targeting of LCs significantly improved anti-HIV immune response without requirement of an adjuvant. Although the co-injection of the TLR-7/8 synthetic ligand, R-848 (resiquimod), with the vaccine, did not enhance significantly the antibody response, it stimulated recruitment of HLA-DR+ inflammatory cells to the site of immunization. This study allowed us to characterize the dynamics of early local events following the injection of a vaccine-targeted epidermal LCs and R-848. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an Empirical Proof of a Promising Concept.

PubMed

Baum, Richard P; Langbein, Thomas; Singh, Aviral; Shahinfar, Mostafa; Schuchardt, Christiane; Volk, Gerd Fabian; Kulkarni, Harshad

2018-02-01

The dose-limiting salivary gland toxicity of 225 Ac-labelled PSMA for treatment of metastatic, castration-resistant prostate cancer remains unresolved. Suppressing the metabolism of the gland by intraparenchymal injections of botulinum toxin appears to be a promising method to reduce off-target uptake. A 68 Ga-PSMA PET/CT scan performed 45 days after injection of 80 units of botulinum toxin A into the right parotid gland in a 63-year-old patient showed a decrease in the SUVmean in the right parotid gland of up to 64% as compared with baseline. This approach could be a significant breakthrough for radioprotection of the salivary glands during PSMA radioligand therapy.

Photodynamic Therapy of the Canine Prostate: Intra-arterial Drug Delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, Ronald B.; Xiao, Zhengwen; Owen, Richard J.

2008-01-15

Purpose. Interstitial photodynamic therapy (PDT) selectively destroys tissue targeted with a photosensitizer and then exposed to light of a specific wavelength. We report a novel delivery method-intra-arterial drug delivery for PDT of the prostate-in a canine model.Methods. To evaluate drug distribution, the prostatovesical artery was selectively cannulated and photosensitizers alone or in conjunction with 99m-technetium-labeled macro-aggregated albumin ({sup 99m}Tc-MAA) were injected via a 3 Fr microcatheter in 8 animals. One dog was followed for 3 months to determine tolerance and toxicity. The remaining animals were euthanized and imaged with whole-body single photon emission CT and gamma counting for radioactivity distribution.more » Photosensitizer distribution was further analyzed by fluorescence confocal microscopy and tissue chemical extraction. To evaluate PDT, the photosensitizer QLT0074 was infused in 3 animals followed by interstitial illumination with 690 nm laser light. Results. Intra-arterial infusion selectively delivered drugs to the prostate, with both radioactivity and photosensitizer levels significantly higher (up to 18 times) than in the surrounding organs (i.e., rectum). With unilateral injection of {sup 99m}Tc-MAA, only the injected half of the prostate showed activity whereas bilateral administration resulted in drug delivery to the entire prostate. PDT resulted in comprehensive damage to the prostate without severe complications or systemic toxicity. Conclusion. Injection of radiolabeled MAA into the prostatovesical artery results in distribution within the prostate with negligible amounts reaching the adjacent organs. PDT also demonstrates selective damage to the prostate, which warrants clinical application in targeted prostate therapies.« less

Optimization of injection molding process parameters for a plastic cell phone housing component

NASA Astrophysics Data System (ADS)

Rajalingam, Sokkalingam; Vasant, Pandian; Khe, Cheng Seong; Merican, Zulkifli; Oo, Zeya

2016-11-01

To produce thin-walled plastic items, injection molding process is one of the most widely used application tools. However, to set optimal process parameters is difficult as it may cause to produce faulty items on injected mold like shrinkage. This study aims at to determine such an optimum injection molding process parameters which can reduce the fault of shrinkage on a plastic cell phone cover items. Currently used setting of machines process produced shrinkage and mis-specified length and with dimensions below the limit. Thus, for identification of optimum process parameters, maintaining closer targeted length and width setting magnitudes with minimal variations, more experiments are needed. The mold temperature, injection pressure and screw rotation speed are used as process parameters in this research. For optimal molding process parameters the Response Surface Methods (RSM) is applied. The major contributing factors influencing the responses were identified from analysis of variance (ANOVA) technique. Through verification runs it was found that the shrinkage defect can be minimized with the optimal setting found by RSM.

Large Genomic Fragment Deletions and Insertions in Mouse Using CRISPR/Cas9

PubMed Central

Satheka, Achim Cchitvsanzwhoh; Togo, Jacques; An, Yao; Humphrey, Mabwi; Ban, Luying; Ji, Yan; Jin, Honghong; Feng, Xuechao; Zheng, Yaowu

2015-01-01

ZFN, TALENs and CRISPR/Cas9 system have been used to generate point mutations and large fragment deletions and insertions in genomic modifications. CRISPR/Cas9 system is the most flexible and fast developing technology that has been extensively used to make mutations in all kinds of organisms. However, the most mutations reported up to date are small insertions and deletions. In this report, CRISPR/Cas9 system was used to make large DNA fragment deletions and insertions, including entire Dip2a gene deletion, about 65kb in size, and β-galactosidase (lacZ) reporter gene insertion of larger than 5kb in mouse. About 11.8% (11/93) are positive for 65kb deletion from transfected and diluted ES clones. High targeting efficiencies in ES cells were also achieved with G418 selection, 46.2% (12/26) and 73.1% (19/26) for left and right arms respectively. Targeted large fragment deletion efficiency is about 21.4% of live pups or 6.0% of injected embryos. Targeted insertion of lacZ reporter with NEO cassette showed 27.1% (13/48) of targeting rate by ES cell transfection and 11.1% (2/18) by direct zygote injection. The procedures have bypassed in vitro transcription by directly co-injection of zygotes or co-transfection of embryonic stem cells with circular plasmid DNA. The methods are technically easy, time saving, and cost effective in generating mouse models and will certainly facilitate gene function studies. PMID:25803037

AAV-mediated targeting of gene expression to the peri-infarct region in rat cortical stroke model.

PubMed

Mätlik, Kert; Abo-Ramadan, Usama; Harvey, Brandon K; Arumäe, Urmas; Airavaara, Mikko

2014-10-30

For stroke patients the recovery of cognitive and behavioral functions is often incomplete. Functional recovery is thought to be mediated largely by connectivity rearrangements in the peri-infarct region. A method for manipulating gene expression in this region would be useful for identifying new recovery-enhancing treatments. We have characterized a way of targeting adeno-associated virus (AAV) vectors to the peri-infarct region of cortical ischemic lesion in rats 2days after middle cerebral artery occlusion (MCAo). We used magnetic resonance imaging (MRI) to show that the altered properties of post-ischemic brain tissue facilitate the spreading of intrastriatally injected nanoparticles toward the infarct. We show that subcortical injection of green fluorescent protein-encoding dsAAV7-GFP resulted in transduction of cells in and around the white matter tract underlying the lesion, and in the cortex proximal to the lesion. A similar result was achieved with dsAAV7 vector encoding the cerebral dopamine neurotrophic factor (CDNF), a protein with therapeutic potential. Viral vector-mediated intracerebral gene delivery has been used before in rodent models of ischemic injury. However, the method of targeting gene expression to the peri-infarct region, after the initial phase of ischemic cell death, has not been described before. We demonstrate a straightforward and robust way to target AAV vector-mediated over-expression of genes to the peri-infarct region in a rat stroke model. This method will be useful for studying the action of specific proteins in peri-infarct region during the recovery process. Copyright © 2014 Elsevier B.V. All rights reserved.

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine ({sup 131}I) metuximab injection: Clinical Phase I/II trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Zhinan; Mi Li; Xu Jing

2006-06-01

Purpose: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine ({sup 131}I) metuximab injection (Licartin), a novel {sup 131}I-labeled HAb18G/CD147-specific monoclonal antibody F(ab'){sub 2} fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. Methods and Materials: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. Results: No life-threatening toxicmore » effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p 0.0019). Conclusion: Iodine ({sup 131}I) metuximab injection is safe and active for HCC patients.« less

Direct memory access transfer completion notification

DOEpatents

Archer, Charles J. , Blocksome; Michael A. , Parker; Jeffrey, J [Rochester, MN

2011-02-15

Methods, systems, and products are disclosed for DMA transfer completion notification that include: inserting, by an origin DMA on an origin node in an origin injection FIFO, a data descriptor for an application message; inserting, by the origin DMA, a reflection descriptor in the origin injection FIFO, the reflection descriptor specifying a remote get operation for injecting a completion notification descriptor in a reflection injection FIFO on a reflection node; transferring, by the origin DMA to a target node, the message in dependence upon the data descriptor; in response to completing the message transfer, transferring, by the origin DMA to the reflection node, the completion notification descriptor in dependence upon the reflection descriptor; receiving, by the origin DMA from the reflection node, a completion packet; and notifying, by the origin DMA in response to receiving the completion packet, the origin node's processing core that the message transfer is complete.

1.5 T augmented reality navigated interventional MRI: paravertebral sympathetic plexus injections.

PubMed

Marker, David R; U Thainual, Paweena; Ungi, Tamas; Flammang, Aaron J; Fichtinger, Gabor; Iordachita, Iulian I; Carrino, John A; Fritz, Jan

2017-01-01

The high contrast resolution and absent ionizing radiation of interventional magnetic resonance imaging (MRI) can be advantageous for paravertebral sympathetic nerve plexus injections. We assessed the feasibility and technical performance of MRI-guided paravertebral sympathetic injections utilizing augmented reality navigation and 1.5 T MRI scanner. A total of 23 bilateral injections of the thoracic (8/23, 35%), lumbar (8/23, 35%), and hypogastric (7/23, 30%) paravertebral sympathetic plexus were prospectively planned in twelve human cadavers using a 1.5 Tesla (T) MRI scanner and augmented reality navigation system. MRI-conditional needles were used. Gadolinium-DTPA-enhanced saline was injected. Outcome variables included the number of control magnetic resonance images, target error of the needle tip, punctures of critical nontarget structures, distribution of the injected fluid, and procedure length. Augmented-reality navigated MRI guidance at 1.5 T provided detailed anatomical visualization for successful targeting of the paravertebral space, needle placement, and perineural paravertebral injections in 46 of 46 targets (100%). A mean of 2 images (range, 1-5 images) were required to control needle placement. Changes of the needle trajectory occurred in 9 of 46 targets (20%) and changes of needle advancement occurred in 6 of 46 targets (13%), which were statistically not related to spinal regions (P = 0.728 and P = 0.86, respectively) and cadaver sizes (P = 0.893 and P = 0.859, respectively). The mean error of the needle tip was 3.9±1.7 mm. There were no punctures of critical nontarget structures. The mean procedure length was 33±12 min. 1.5 T augmented reality-navigated interventional MRI can provide accurate imaging guidance for perineural injections of the thoracic, lumbar, and hypogastric sympathetic plexus.

Changes in contractile properties of muscles receiving repeat injections of botulinum toxin (Botox).

PubMed

Fortuna, Rafael; Vaz, Marco Aurélio; Youssef, Aliaa Rehan; Longino, David; Herzog, Walter

2011-01-04

Botulinum toxin type A (BTX-A) is a frequently used therapeutic tool to denervate muscles in the treatment of neuromuscular disorders. Although considered safe by the US Food and Drug Administration, BTX-A can produce adverse effects in target and non-target muscles. With an increased use of BTX-A for neuromuscular disorders, the effects of repeat injections of BTX-A on strength, muscle mass and structure need to be known. Therefore, the purpose of this study was to investigate the changes in strength, muscle mass and contractile material in New Zealand White (NZW) rabbits. Twenty NZW rabbits were divided into 4 groups: control and 1, 3 and 6 months of unilateral, repeat injections of BTX-A into the quadriceps femoris. Outcome measures included knee extensor torque, muscle mass and the percentage of contractile material in the quadriceps muscles of the target and non-injected contralateral hindlimbs. Strength in the injected muscles was reduced by 88%, 89% and 95% in the 1, 3 and 6 months BTX-A injected hindlimbs compared to controls. Muscle mass was reduced by 50%, 42% and 31% for the vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM), respectively, at 1 month, by 68%, 51% and 50% at 3 months and by 76%, 44% and 13% at 6 months. The percentage of contractile material was reduced for the 3 and 6 months animals to 80-64%, respectively, and was replaced primarily by fat. Similar, but less pronounced results were also observed for the quadriceps muscles of the contralateral hindlimbs, suggesting that repeat BTX-A injections cause muscle atrophy and loss of contractile tissue in target muscles and also in non-target muscles that are far removed from the injection site. Copyright © 2010 Elsevier Ltd. All rights reserved.

Do skeletal muscle properties recover following repeat onabotulinum toxin A injections?

PubMed

Fortuna, Rafael; Horisberger, Monika; Vaz, Marco Aurélio; Herzog, Walter

2013-09-27

Onabotulinum toxin A (BTX-A) is a frequently used treatment modality to relax spastic muscles by preventing acetylcholine release at the motor nerve endings. Although considered safe, previous studies have shown that BTX-A injections cause muscle atrophy and deterioration in target and non-target muscles. Ideally, muscles should fully recover following BTX-A treatments, so that muscle strength and performance are not affected in the long-term. However, systematic, long-term data on the recovery of muscles exposed to BTX-A treatments are not available, thus practice guidelines on the frequency and duration of BTX-A injections, and associated recovery protocols, are based on clinical experience with little evidence-based information. Therefore, the purpose of this study was to investigate muscle recovery following a six months, monthly BTX-A injection (3.5 U/kg) protocol. Twenty seven skeletally mature NZW rabbits were divided into 5 groups: Control (n=5), zero month recovery - BTX-A+0M (n=5), one month recovery - BTX-A+1M (n=5), three months recovery - BTX-A+3M (n=5), and six months recovery - BTX-A+6M (n=7). Knee extensor strength, muscle mass and percent contractile material in injected and contralateral non-injected muscles was measured at each point of recovery. Strength and muscle mass were partially and completely recovered in injected and contralateral non-injected muscles for BTX-A+6M group animals, respectively. The percent of contractile material partially recovered in the injected, but did not recover in the contralateral non-injected muscles. We conclude from these results that neither target nor non-target muscles fully recover within six months of a BTX-A treatment protocol and that clinical studies on muscle recovery should be pursued. © 2013 Elsevier Ltd. All rights reserved.

NON-INVASIVE RADIOFREQUENCY ABLATION OF CANCER TARGETED BY GOLD NANOPARTICLES

PubMed Central

Cardinal, Jon; Klune, John Robert; Chory, Eamon; Jeyabalan, Geetha; Kanzius, John S.; Nalesnik, Michael; Geller, David A.

2008-01-01

Introduction Current radiofrequency ablation (RFA) techniques require invasive needle placement and are limited by accuracy of targeting. The purpose of this study was to test a novel non-invasive radiowave machine that uses RF energy to thermally destroy tissue. Gold nanoparticles were designed and produced to facilitate tissue heating by the radiowaves. Methods A solid state radiowave machine consisting of a power generator and transmitting/receiving couplers which transmit radiowaves at 13.56 MHz was used. Gold nanoparticles were produced by citrate reduction and exposed to the RF field either in solutions testing or after incubation with HepG2 cells. A rat hepatoma model using JM-1 cells and Fisher rats was employed using direct injection of nanoparticles into the tumor to focus the radiowaves for select heating. Temperatures were measured using a fiber-optic thermometer for real-time data. Results Solutions containing gold nanoparticles heated in a time- and power-dependent manner. HepG2 liver cancer cells cultured in the presence of gold nanoparticles achieved adequate heating to cause cell death upon exposure to the RF field with no cytotoxicity attributable to the gold nanoparticles themselves. In vivo rat exposures at 35W using gold nanoparticles for tissue injection resulted in significant temperature increases and thermal injury at subcutaneous injection sites as compared to vehicle (water) injected controls. Discussion These data show that non-invasive radiowave thermal ablation of cancer cells is feasible when facilitated by gold nanoparticles. Future studies will focus on tumor selective targeting of nanoparticles for in vivo tumor destruction. PMID:18656617

Selective Gene Transfection of Individual Cells In Vitro with Plasmonic Nanobubbles

PubMed Central

Lukianova-Hleb, Ekaterina; Samaniego, Adam P.; Wen, Jianguo; Metelitsa, Leonid; Chang, Chung-Che; Lapotko, Dmitri

2011-01-01

Gene delivery and transfection of eukaryotic cells is widely used for research and for developing gene cell therapy. However, the existing methods lack selectivity, efficacy and safety when heterogeneous cell systems must be treated. We report a new method that employs plasmonic nanobubbles (PNBs) for delivery and transfection. A PNB is a novel, tunable cellular agent with a dual mechanical and optical action due to the formation of the vapor nanobubble around a transiently heated gold nanoparticle upon its exposure to a laser pulse. PNBs enabled the mechanical injection of the extracellular cDNA plasmid into the cytoplasm of individual target living cells, cultured leukemia cells and human CD34+CD117+ stem cells and expression of a green fluorescent protein (GFP) in those cells. PNB generation and lifetime correlated with the expression of green fluorescent protein in PNB-treated cells. Optical scattering by PNBs additionally provided the detection of the target cells and the guidance of cDNA injection at single cell level. In both cell models PNBs demonstrated a gene transfection effect in a single pulse treatment with high selectivity, efficacy and safety. Thus, PNBs provided targeted gene delivery at the single cell level in a single pulse procedure that can be used for safe and effective gene therapy. PMID:21315120

Selective gene transfection of individual cells in vitro with plasmonic nanobubbles.

PubMed

Lukianova-Hleb, Ekaterina Y; Samaniego, Adam P; Wen, Jianguo; Metelitsa, Leonid S; Chang, Chung-Che; Lapotko, Dmitri O

2011-06-10

Gene delivery and transfection of eukaryotic cells are widely used for research and for developing gene cell therapy. However, the existing methods lack selectivity, efficacy and safety when heterogeneous cell systems must be treated. We report a new method that employs plasmonic nanobubbles (PNBs) for delivery and transfection. A PNB is a novel, tunable cellular agent with a dual mechanical and optical action due to the formation of the vapor nanobubble around a transiently heated gold nanoparticle upon its exposure to a laser pulse. PNBs enabled the mechanical injection of the extracellular cDNA plasmid into the cytoplasm of individual target living cells, cultured leukemia cells and human CD34+ CD117+ stem cells and expression of a green fluorescent protein (GFP) in those cells. PNB generation and lifetime correlated with the expression of green fluorescent protein in PNB-treated cells. Optical scattering by PNBs additionally provided the detection of the target cells and the guidance of cDNA injection at single cell level. In both cell models PNBs demonstrated a gene transfection effect in a single pulse treatment with high selectivity, efficacy and safety. Thus, PNBs provided targeted gene delivery at the single cell level in a single pulse procedure that can be used for safe and effective gene therapy. Copyright © 2011 Elsevier B.V. All rights reserved.

Biomedical HIV prevention including pre-exposure prophylaxis and opiate agonist therapy for women who inject drugs: State of research and future directions

PubMed Central

Page, Kimberly; Tsui, Judith; Maher, Lisa; Choopanya, Kachit; Vanichseni, Suphak; Mock, Philip A.; Celum, Connie; Martin, Michael

2015-01-01

Women who inject drugs are at higher risk of HIV compared to their male counterparts as a result of multiple factors including biological, behavioral and socio-structural, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this paper, we discuss the need for expanded prevention interventions for women who inject drugs, focusing on two safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). While both interventions are well researched they have not been well examined in the context of gender. We discuss the drivers of women injectors’ higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for women who inject drugs. There is substantial potential for impact of OAT and PrEP programs for women who inject drugs in the context of broader gender-responsive HIV prevention initiatives. While awaiting efficacy data on other biomedical approaches in the HIV prevention research ‘pipeline’, we propose that the scale up and implementation of these proven, safe, and effective interventions are needed now. PMID:25978484

Validation approach for a fast and simple targeted screening method for 75 antibiotics in meat and aquaculture products using LC-MS/MS.

PubMed

Dubreil, Estelle; Gautier, Sophie; Fourmond, Marie-Pierre; Bessiral, Mélaine; Gaugain, Murielle; Verdon, Eric; Pessel, Dominique

2017-04-01

An approach is described to validate a fast and simple targeted screening method for antibiotic analysis in meat and aquaculture products by LC-MS/MS. The strategy of validation was applied for a panel of 75 antibiotics belonging to different families, i.e., penicillins, cephalosporins, sulfonamides, macrolides, quinolones and phenicols. The samples were extracted once with acetonitrile, concentrated by evaporation and injected into the LC-MS/MS system. The approach chosen for the validation was based on the Community Reference Laboratory (CRL) guidelines for the validation of screening qualitative methods. The aim of the validation was to prove sufficient sensitivity of the method to detect all the targeted antibiotics at the level of interest, generally the maximum residue limit (MRL). A robustness study was also performed to test the influence of different factors. The validation showed that the method is valid to detect and identify 73 antibiotics of the 75 antibiotics studied in meat and aquaculture products at the validation levels.

A non-inheritable maternal Cas9-based multiple-gene editing system in mice.

PubMed

Sakurai, Takayuki; Kamiyoshi, Akiko; Kawate, Hisaka; Mori, Chie; Watanabe, Satoshi; Tanaka, Megumu; Uetake, Ryuichi; Sato, Masahiro; Shindo, Takayuki

2016-01-28

The CRISPR/Cas9 system is capable of editing multiple genes through one-step zygote injection. The preexisting method is largely based on the co-injection of Cas9 DNA (or mRNA) and guide RNAs (gRNAs); however, it is unclear how many genes can be simultaneously edited by this method, and a reliable means to generate transgenic (Tg) animals with multiple gene editing has yet to be developed. Here, we employed non-inheritable maternal Cas9 (maCas9) protein derived from Tg mice with systemic Cas9 overexpression (Cas9 mice). The maCas9 protein in zygotes derived from mating or in vitro fertilization of Tg/+ oocytes and +/+ sperm could successfully edit the target genome. The efficiency of such maCas9-based genome editing was comparable to that of zygote microinjection-based genome editing widely used at present. Furthermore, we demonstrated a novel approach to create "Cas9 transgene-free" gene-modified mice using non-Tg (+/+) zygotes carrying maCas9. The maCas9 protein in mouse zygotes edited nine target loci simultaneously after injection with nine different gRNAs alone. Cas9 mouse-derived zygotes have the potential to facilitate the creation of genetically modified animals carrying the Cas9 transgene, enabling repeatable genome engineering and the production of Cas9 transgene-free mice.

Evaluating the functional outcomes of ultrasound-guided botulinum toxin type A injections using the Euro-musculus approach for upper limb spasticity treatment in post-stroke patients; an observational study.

PubMed

Buyukavci, Raikan; Akturk, Semra; Ersoy, Yüksel

2018-02-07

Ultrasound-guided botulinum toxin type A injection is an effective treatment for spasticity. Euro-musculus spasticity approach is a new method for administering injections to the correct point of the correct muscle. The clinical outcomes of this practical approach is not yet available in the literature. The purpose of this study was to evaluate the effects on spasticity and the functional outcomes of ultrasound guided botulinum toxin type A injections via the Euro-musculus spasticity approach to treat upper limb spasticity in post-stroke patients. An observational study. Inpatient post-stroke patients. Twenty five post-stroke patients with post-stroke upper limb spasticity were recruited. The ultrasound-guided botulinum toxin type A injections were administered into the spastic target muscles using the Euro-musculus spasticity approach, and all of the patients were enrolled in rehabilitation programmes after the injections. This research included the innervation zone and injection site figures and ultrasound images of each muscle in the upper limb. The degree of spasticity was assessed via the Modified Ashworth Scale and the upper limb motor function via the Fugl Meyer Upper Extremity Scale at the baseline and 4 and 12 weeks after the botulinum toxin type A injection. Significant decreases in the Modified Ashworth Scale scores of the upper limb flexor muscle tone measured 4 and 12 weeks after the botulinum toxin type A injection were found when compared to the baseline scores (p<0.025). When compared with the baseline Fugl Meyer Upper Extremity subgroup scores, the sitting position, wrist and total scores at 4 and 12 weeks were significantly improved (p<0.025). However, only the Fugl Meyer Upper Extremity hand scores were significantly improved 12 weeks after the injection (p<0.025). Ultrasound-guided botulinum toxin type A injection via the Euro- musculus spasticity approach is a practical and effective method for administering injections to the correct point of the correct muscle. Ultrasound-guided botulinum toxin type A injections combined with rehabilitation programmes decrease spasticity and improve the upper extremity motor functions in stroke patients. This new approach for ultrasound- guided botulinum toxin type A injection is very practical and effective method for upper extremity spasticity.

Numerical Study on Focusing of Ultrasounds in Microbubble-enhanced HIFU

NASA Astrophysics Data System (ADS)

Matsumoto, Yoichiro; Okita, Kohei; Takagi, Shu

2011-11-01

The injection of microbubbles into the target tissue enhances tissue heating in High-Intensity Focused Ultrasound therapy, via inertial cavitation. The control of the inertial cavitation is required to achieve the efficient tissue ablation. Microbubbles between a transducer and a target disturb the ultrasound propagation depending on the conditions. A method to clear such microbubbles has been proposed by Kajiyama et al. [Physics Procedia 3 (2010) 305-314]. In the method, the irradiation of intense ultrasounds with a burst waveform fragmentize microbubbles in the pathways before the irradiation of ultrasounds for tissue heating. The vitro experiment using a gel containing microbubbles has showed that the method enables to heat the target correctly by controlling the microbubble distribution. Following the experiment, we simulate the focusing of ultrasounds through a mixture containing microbubbles with considering the size and number density distributions in space. The numerical simulation shows that the movement of the heating region from the transducer side to the target by controlling the microbubble distributions. The numerical results elucidate well the experimental ones.

Capabilities of Direct Sample Introduction - Comprehensive Two-Dimensional Gas Chromatgraphy-Time-of-Flight Mass Spectrometry to Analyze Organic Chemicals of Interest in Fish Oils

USDA-ARS?s Scientific Manuscript database

Most analytical methods for persistent organic pollutants (POPs) focus on targeted analytes. Therefore, analysis of multiple classes of POPs typically entails several sample preparations, fractionations, and injections, whereas other chemicals of possible interest are neglected. To analyze a wider...

A bacterial type III secretion-based protein delivery tool for broad applications in cell biology.

PubMed

Ittig, Simon J; Schmutz, Christoph; Kasper, Christoph A; Amstutz, Marlise; Schmidt, Alexander; Sauteur, Loïc; Vigano, M Alessandra; Low, Shyan Huey; Affolter, Markus; Cornelis, Guy R; Nigg, Erich A; Arrieumerlou, Cécile

2015-11-23

Methods enabling the delivery of proteins into eukaryotic cells are essential to address protein functions. Here we propose broad applications to cell biology for a protein delivery tool based on bacterial type III secretion (T3S). We show that bacterial, viral, and human proteins, fused to the N-terminal fragment of the Yersinia enterocolitica T3S substrate YopE, are effectively delivered into target cells in a fast and controllable manner via the injectisome of extracellular bacteria. This method enables functional interaction studies by the simultaneous injection of multiple proteins and allows the targeting of proteins to different subcellular locations by use of nanobody-fusion proteins. After delivery, proteins can be freed from the YopE fragment by a T3S-translocated viral protease or fusion to ubiquitin and cleavage by endogenous ubiquitin proteases. Finally, we show that this delivery tool is suitable to inject proteins in living animals and combine it with phosphoproteomics to characterize the systems-level impact of proapoptotic human truncated BID on the cellular network. © 2015 Ittig et al.

Indocyanine green fluorescence-navigated thoracoscopic anatomical segmentectomy

PubMed Central

Okumura, Sakae; Nakao, Masayuki; Matsuura, Yosuke; Nakagawa, Ken

2017-01-01

Background To evaluate the feasibility and efficacy of thoracoscopic anatomical segmentectomy (TS-S) using three-dimensional computed tomography (3D-CT) reconstruction and indocyanine green-fluorescence (ICGF) navigation. Methods Twenty TS-S procedures were performed for 15 primary lung cancers and 5 metastatic lung tumors. Preoperatively we evaluated the target segmental pulmonary artery and created a virtual intersegmental plane using 3D-CT reconstruction. Intraoperatively, the target segmental artery and bronchus were divided, and after intravenous systemic injection of indocyanine green (ICG, 0.25 mg/kg), ICGF of the non-target segments (NTS) was observed using infrared thoracoscopy (KARL STORZ Endoskope Japan K.K., Tokyo, Japan). We marked the border between target and NTS with electrocautery and divided the lung parenchyma along this border using electrocautery or staples. Strength of contrast between target and NTS was quantified as contrast index (CI) and compared over time. Results ICGF provided demarcation of sufficient clarity and duration to mark the lung surface in 19 patients (95%). TS-S was successfully performed in all patients. Mean operative duration was 186 min (90–310 min) and mean blood loss was 30 mL (0–107 mL). Demarcation appeared 20 s (10–100 s) after injection of ICG, and ICGF lasted 180 s (90–300 s). CI peaked 30 s after the appearance of ICGF and decreased over time. Effective contrast continued for 70 s (30–116 s), which was sufficient to mark the line of demarcation. There were no complications attributable to this method. Conclusions ICGF navigation is a safe and effective technique for TS-S. PMID:29078643

Generation of gene-modified goats targeting MSTN and FGF5 via zygote injection of CRISPR/Cas9 system

PubMed Central

Wang, Xiaolong; Yu, Honghao; Lei, Anmin; Zhou, Jiankui; Zeng, Wenxian; Zhu, Haijing; Dong, Zhiming; Niu, Yiyuan; Shi, Bingbo; Cai, Bei; Liu, Jinwang; Huang, Shuai; Yan, Hailong; Zhao, Xiaoe; Zhou, Guangxian; He, Xiaoling; Chen, Xiaoxu; Yang, Yuxin; Jiang, Yu; Shi, Lei; Tian, Xiue; Wang, Yongjun; Ma, Baohua; Huang, Xingxu; Qu, Lei; Chen, Yulin

2015-01-01

Recent advances in the study of the CRISPR/Cas9 system have provided a precise and versatile approach for genome editing in various species. However, the applicability and efficiency of this method in large animal models, such as the goat, have not been extensively studied. Here, by co-injection of one-cell stage embryos with Cas9 mRNA and sgRNAs targeting two functional genes (MSTN and FGF5), we successfully produced gene-modified goats with either one or both genes disrupted. The targeting efficiency of MSTN and FGF5 in cultured primary fibroblasts was as high as 60%, while the efficiency of disrupting MSTN and FGF5 in 98 tested animals was 15% and 21% respectively, and 10% for double gene modifications. The on- and off-target mutations of the target genes in fibroblasts, as well as in somatic tissues and testis of founder and dead animals, were carefully analyzed. The results showed that simultaneous editing of several sites was achieved in large animals, demonstrating that the CRISPR/Cas9 system has the potential to become a robust and efficient gene engineering tool in farm animals, and therefore will be critically important and applicable for breeding. PMID:26354037

Self-pacing direct memory access data transfer operations for compute nodes in a parallel computer

DOEpatents

Blocksome, Michael A

2015-02-17

Methods, apparatus, and products are disclosed for self-pacing DMA data transfer operations for nodes in a parallel computer that include: transferring, by an origin DMA on an origin node, a RTS message to a target node, the RTS message specifying an message on the origin node for transfer to the target node; receiving, in an origin injection FIFO for the origin DMA from a target DMA on the target node in response to transferring the RTS message, a target RGET descriptor followed by a DMA transfer operation descriptor, the DMA descriptor for transmitting a message portion to the target node, the target RGET descriptor specifying an origin RGET descriptor on the origin node that specifies an additional DMA descriptor for transmitting an additional message portion to the target node; processing, by the origin DMA, the target RGET descriptor; and processing, by the origin DMA, the DMA transfer operation descriptor.

Establishment of A431 cell membrane chromatography-RPLC method for screening target components from Radix Caulophylli.

PubMed

Hou, Xiaofang; Wang, Sicen; Hou, Jingjing; He, Langchong

2011-03-01

We describe here an analytical method of A431 cell membrane chromatography (A431/CMC) (CMC, cell membrane chromatography) combined with RPLC for recognition, separation, and identification of target components from traditional Chinese medicines (TCMs) Radix Caulophylli. The A431 cells with high expressed epidermal growth factor receptor (EGFR) were used to prepare the stationary phase in the CMC model. Retention fractions on the A431-CMC model were collected using an automated fraction collection and injection module (FC/I). Each fraction was analyzed by RPLC under the optimized conditions. Gefitinib and erlotinib were used as standard compounds to investigate the suitability and reliability of the A431 cell membrane chromatography-RPLC method prior to screening target component from Radix Caulophylli total alkaloids. The results indicated that caulophine and taspine were the target component acting on the epidermal growth factor receptor. This method could be an efficient way in drug discovery using natural medicinal herbs as a source of novel compounds. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Single-step generation of rabbits carrying a targeted allele of the tyrosinase gene using CRISPR/Cas9.

PubMed

Honda, Arata; Hirose, Michiko; Sankai, Tadashi; Yasmin, Lubna; Yuzawa, Kazuaki; Honsho, Kimiko; Izu, Haruna; Iguchi, Atsushi; Ikawa, Masahito; Ogura, Atsuo

2015-01-01

Targeted genome editing of nonrodent mammalian species has provided the potential for highly accurate interventions into gene function in humans and the generation of useful animal models of human diseases. Here we show successful clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas)-mediated gene targeting via circular plasmid injection in rabbits. The rabbit tyrosinase gene (TYR) was effectively disrupted, and we confirmed germline transmission by pronuclear injection of a circular plasmid expressing humanized Cas9 (hCas9) and single-guide RNA. Direct injection into pronuclear stage zygotes was possible following an in vitro validation assay. Neither off-target mutagenesis nor hCas9 transgenesis was detected in any of the genetically targeted pups and embryos examined. Gene targeting with this rapid and simplified strategy will help accelerate the development of translational research using other nonrodent mammalian species.

Single-step generation of rabbits carrying a targeted allele of the tyrosinase gene using CRISPR/Cas9

PubMed Central

Honda, Arata; Hirose, Michiko; Sankai, Tadashi; Yasmin, Lubna; Yuzawa, Kazuaki; Honsho, Kimiko; Izu, Haruna; Iguchi, Atsushi; Ikawa, Masahito; Ogura, Atsuo

2014-01-01

Targeted genome editing of nonrodent mammalian species has provided the potential for highly accurate interventions into gene function in humans and the generation of useful animal models of human diseases. Here we show successful clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas)-mediated gene targeting via circular plasmid injection in rabbits. The rabbit tyrosinase gene (TYR) was effectively disrupted, and we confirmed germline transmission by pronuclear injection of a circular plasmid expressing humanized Cas9 (hCas9) and single-guide RNA. Direct injection into pronuclear stage zygotes was possible following an in vitro validation assay. Neither off-target mutagenesis nor hCas9 transgenesis was detected in any of the genetically targeted pups and embryos examined. Gene targeting with this rapid and simplified strategy will help accelerate the development of translational research using other nonrodent mammalian species. PMID:25195632

Dedicated exhaust gas recirculation control systems and methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sczomak, David P.; Narayanaswamy, Kushal; Keating, Edward J.

An engine control system of a vehicle includes a fuel control module that controls fuel injection of a first cylinder of an engine based on a first target air/fuel ratio that is fuel lean relative to a stoichiometric air/fuel ratio and that controls fuel injection of a second cylinder of the engine based on a second target air/fuel ratio that is fuel rich relative to stoichiometry. The first cylinder outputs exhaust to a first three way catalyst (TWC), and the second cylinder outputs exhaust to an exhaust gas recirculation (EGR) valve. An EGR control module controls opening of the EGRmore » valve to: (i) a second TWC that reacts with nitrogen oxides (NOx) in the exhaust and outputs ammonia to a selective catalytic reduction (SCR) catalyst; and (ii) a conduit that recirculates exhaust back to an intake system of the engine.« less

Direct memory access transfer completion notification

DOEpatents

Archer, Charles J.; Blocksome, Michael A.; Parker, Jeffrey J.

2010-08-17

Methods, apparatus, and products are disclosed for DMA transfer completion notification that include: inserting, by an origin DMA engine on an origin compute node in an injection FIFO buffer, a data descriptor for an application message to be transferred to a target compute node on behalf of an application on the origin compute node; inserting, by the origin DMA engine, a completion notification descriptor in the injection FIFO buffer after the data descriptor for the message, the completion notification descriptor specifying an address of a completion notification field in application storage for the application; transferring, by the origin DMA engine to the target compute node, the message in dependence upon the data descriptor; and notifying, by the origin DMA engine, the application that the transfer of the message is complete, including performing a local direct put operation to store predesignated notification data at the address of the completion notification field.

Development of position measurement unit for flying inertial fusion energy target

NASA Astrophysics Data System (ADS)

Tsuji, R.; Endo, T.; Yoshida, H.; Norimatsu, T.

2016-03-01

We have reported the present status in the development of a position measurement unit (PMU) for a flying inertial fusion energy (IFE) target. The PMU, which uses Arago spot phenomena, is designed to have a measurement accuracy smaller than 1 μm. By employing divergent, pulsed orthogonal laser beam illumination, we can measure the time and the target position at the pulsed illumination. The two-dimensional Arago spot image is compressed into one-dimensional image by a cylindrical lens for real-time processing. The PMU are set along the injection path of the flying target. The local positions of the target in each PMU are transferred to the controller and analysed to calculate the target trajectory. Two methods are presented to calculate the arrival time and the arrival position of the target at the reactor centre.

A Unitary Anesthetic Binding Site at High Resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vedula, L. Sangeetha; Brannigan, Grace; Economou, Nicoleta J.

2009-10-21

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA{sub A} receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA{sub A} receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show thatmore » apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA{sub A} receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.« less

A Unitary Anesthetic Binding Site at High Resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

L Vedula; G Brannigan; N Economou

2011-12-31

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA{sub A} receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA{sub A} receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show thatmore » apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA{sub A} receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.« less

A Unitary Anesthetic-Binding Site at High Resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vedula, L.; Brannigan, G; Economou, N

2009-01-01

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABAA receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA{sub A} receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show that apoferritinmore » also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA{sub A} receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.« less

Optimizing gene transfer to conventional outflow cells in living mouse eyes

PubMed Central

Li, G; Gonzalez, P; Camras, LJ; Navarro, I; Qiu, J; Challa, P; Stamer, WD

2013-01-01

The mouse eye has physiological and genetic advantages to study conventional outflow function. However, its small size and shallow anterior chamber presents technical challenges to efficient intracameral delivery of genetic material to conventional outflow cells. The goal of this study was to optimize methods to overcome this technical hurdle, without damaging ocular structures or compromising outflow function. Gene targeting was monitored by immunofluorescence microscopy after transduction of adenovirus encoding green fluorescent protein driven by a CMV promoter. Guided by a micromanipulator and stereomicroscope, virus was delivered intracamerally to anesthetized mice by bolus injection using 33 gauge needle attached to Hamilton syringe or infusion with glass micropipette connected to syringe pump. The total number of particles introduced remained constant, while volume of injected virus solution (3–10 µl) was varied for each method and time of infusion (3–40 min) tested. Outflow facility and intraocular pressure were monitored invasively using established techniques. Unlike bolus injections or slow infusions, introduction of virus intracamerally during rapid infusions (3 min) at any volume tested preferentially targeted trabecular meshwork and Schlemm's canal cells, with minimal transduction of neighboring cells. While infusions resulted in transient intraocular pressure spikes (commensurate with volume infused, Δ40–70 mmHg), eyes typically recovered within 60 minutes. Transduced eyes displayed normal outflow facility and tissue morphology 3–6 days after infusions. Taken together, fast infusion of virus solution in small volumes intracamerally is a novel and effective method to selectively deliver agents to conventional outflow cells in living mice. PMID:23337742

Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye.

PubMed

Patel, Samirkumar R; Berezovsky, Damian E; McCarey, Bernard E; Zarnitsyn, Vladimir; Edelhauser, Henry F; Prausnitz, Mark R

2012-07-01

This study seeks to determine the intraocular pharmacokinetics of molecules and particles injected into the suprachoroidal space of the rabbit eye in vivo using a hollow microneedle. Suprachoroidal injections of fluorescein and fluorescently tagged dextrans (40 and 250 kDa), bevacizumab, and polymeric particles (20 nm to 10 μm in diameter) were performed using microneedles in New Zealand white rabbits. The fluorescence intensity within the eye was monitored in each animal using an ocular fluorophotometer to determine the distribution of the injected material in the eye over time as compared with intravitreal injection of fluorescein. Fundus photography and histology were performed as well. Molecules and particles injected near the limbus using a microneedle flowed circumferentially around the eye within the suprachoroidal space. By targeting the suprachoroidal space, the concentration of injected materials was at least 10-fold higher in the back of the eye tissues than in anterior tissues. In contrast, intravitreal injection of fluorescein targeted the vitreous humor with no significant selectivity for posterior versus anterior segment tissues. Half-lives in the suprachoroidal space for molecules of molecular weight from 0.3 to 250 kDa ranged from 1.2 to 7.9 hours. In contrast, particles ranging in size from 20 nm to 10 μm remained primarily in the suprachoroidal space and choroid for a period of months and did not clear the eye. No adverse effects of injection into the suprachoroidal space were observed. Injection into the suprachoroidal space using a microneedle offers a simple and minimally invasive way to target the delivery of drugs to the choroid and retina.

Investigating an organ-targeting platform based on hydroxyapatite nanoparticles using a novel in situ method of radioactive ¹²⁵Iodine labeling.

PubMed

Ignjatović, Nenad; Vranješ Djurić, Sanja; Mitić, Zarko; Janković, Drina; Uskoković, Dragan

2014-10-01

In this study, we have investigated the synthesis of nanoparticles of hydroxyapatite (HAp) and hydroxyapatite coated with chitosan (HAp/Ch) and the chitosan-poly-d,l-lactide-co-glycolide polymer blend (HAp/Ch-PLGA) as an organ-targeting system. We have examined and defined the final destination, as well as the dynamics and the pathways of the synthesized particles following intravenous administration in vivo. The XRD, ZP, FT-IR and SEM analyses have confirmed that the hydroxyapatite nanoparticles with d50=72 nm are coated with polymers. Radioactive 125-Iodine ((125)I), a low energy gamma emitter, was used to develop a novel in situ method for the radiolabeling of particles and investigation of their biodistribution. (125)I-labeled particles exhibited high stability in saline and serum over the second day, which justified their use in the following in vivo studies. The biodistribution of (125)I-labeled particles after intravenous injection in rats differed significantly: HAp particles mostly targeted the liver, HAp/Ch the spleen and the liver, while HAp/Ch-PLGA targeted the lungs. Twenty-four hours post injection, HAp particles were excreted completely, while both (125)I-HAp/Ch and (125)I-HAp/Ch-PLGA were retained in the body for a prolonged period of time with more than 20% of radioactivity still found in different organs. Copyright © 2014 Elsevier B.V. All rights reserved.

Highly efficient generation of knock-in transgenic medaka by CRISPR/Cas9-mediated genome engineering.

PubMed

Watakabe, Ikuko; Hashimoto, Hisashi; Kimura, Yukiko; Yokoi, Saori; Naruse, Kiyoshi; Higashijima, Shin-Ichi

2018-01-01

Medaka ( Oryzias latipes ) is a popular animal model used in vertebrate genetic analysis. Recently, an efficient (~ 30%) knock-in system via non-homologous end joining (NHEJ) was established in zebrafish using the CRISPR/Cas9 system. If the same technique were applicable in medaka, it would greatly expand the usefulness of this model organism. The question of the applicability of CRISPR/Cas9 in medaka, however, has yet to be addressed. We report the highly efficient generation of knock-in transgenic medaka via non-homologous end joining (NHEJ). Donor plasmid containing a heat-shock promoter and a reporter gene was co-injected with a short guide RNA (sgRNA) targeted for genome digestion, an sgRNA targeted for donor plasmid digestion, and Cas9 mRNA. Broad transgene expression in the expression domain of a target gene was observed in approximately 25% of injected embryos. By raising these animals, we established stable knock-in transgenic fish with several different constructs for five genetic loci, obtaining transgenic founders at efficiencies of > 50% for all five loci. Further, we show that the method is useful for obtaining mutant alleles. In the experiments where transgene integrations were targeted between the transcription start site and the initiation methionine, the resultant transgenic fish became mutant alleles. With its simplicity, design flexibility, and high efficiency, we propose that CRISPR/Cas9-mediated knock-in via NHEJ will become a standard method for the generation of transgenic and mutant medaka.

The Hydrodynamics of Needle-Free Intradermal Jet Injection

NASA Astrophysics Data System (ADS)

Simmons, Jonathan; Marston, Jeremy; Fisher, Paul; Broderick, Kate

2017-11-01

Needle-free methods of drug delivery circumvent the drawbacks associated with the use of hypodermic needles such as needle-stick injuries, needle-phobia, cross contamination and disposal. Furthermore, pioneering DNA-based vaccines that aim to treat cancer and fight infectious diseases, such as HIV, Ebola and Zika, require precise deposition into the skin to target the immune response producing cells found only in the epidermis and dermis. Intradermal (ID) delivery can be achieved using a needle and the Mantoux technique but this requires a highly skilled technician and so extensive use of DNA vaccines calls for an alternative method of delivery. One option is jet injection which has been employed in mass vaccination programs for intramuscular or subcutaneous delivery and is used by some diabetic patients to inject insulin. In this talk I will present results from our ongoing ex-vivo experimental study into ID jet injection. Ultra-high-speed imaging is used to visualize the process of the jet exiting the nozzle and striking excised skin. A skin bleb grows as liquid is deposited within the skin. I will discuss how the control parameters, such as the rheological profile of the liquid and the stand-off distance, influence the volume of liquid successfully delivered intradermally.

Intra-articular corticoid injection induces circulating glucocorticoid bioactivity and systemic immune activation in juvenile idiopathic arthritis.

PubMed

Rintamäki, H; Tamm, K; Vaarala, O; Sidoroff, M; Honkanen, V; Raivio, T; Jänne, Oa; Kolho, K-L

2011-01-01

To study the systemic effects of intra-articular (IA) glucocorticoid (GC) injections in juvenile idiopathic arthritis (JIA). The study group comprised 21 JIA patients being treated with IA methylprednisolone [MP (n = 15) or MP plus triamcinolone hexacetonide (THA) (n = 6)] prescribed on clinical indications. The systemic effect of MP was assessed by measuring circulating glucocorticoid bioactivity (GBA) with a recombinant cell transactivation assay 7 and 24 h after the IA injections, and after 2 months. The systemic immunological responses were studied with a novel assay for testing patient serum-induced changes in the secretion of interferon (IFN)-γ and interleukin (IL)-5 from target cells. Administration of IA GC induced serum GBA (p = 0.001) and suppressed circulating cortisol levels (p = 0.002) 7 h after the injection. Serum withdrawn 24 h after the IA injection induced less IL-5 secretion from mitogen-activated target cells when compared with pre-treatment sera (p = 0.036). This decrease in target cell T helper (Th)2 response (IL-5) was MP dose related (r = -0.550, p = 0.018). High IL-5 secretion from target cells prior to the IA injections was associated with good clinical outcome at 2 months, seen as a low number of active (p = 0.044) and restricted joints (p = 0.049). IA GC injections have systemic effects that are reflected in the serum as an immediate elevation of GBA, a decrease of endogenous cortisol as well as a suppressive effect of patient serum on target cell IL-5 secretion. These systemic effects may play a role in the attenuation of disease activity.

Multimodal fusion imaging ensemble for targeted sentinel lymph node management: initial results of an innovative promising approach for anatomically difficult lymphatic drainage in different tumour entities.

PubMed

Maza, Sofiane; Taupitz, Mathias; Taymoorian, Kasra; Winzer, Klaus Jürgen; Rückert, Jens; Paschen, Christian; Räber, Gert; Schneider, Sylke; Trefzer, Uwe; Munz, Dieter L

2007-03-01

There are situations where exact identification and localisation of sentinel lymph nodes (SLNs) are very difficult using lymphoscintigraphy, a hand-held gamma probe and vital dye, either a priori or a posteriori. We developed a new method using a simultaneous injection of two lymphotropic agents for exact topographical tomographic localisation and biopsy of draining SLNs. The purpose of this prospective pilot study was to investigate the feasibility and efficacy of this method ensemble. Fourteen patients with different tumour entities were enrolled. A mixture of (99m)Tc-nanocolloid and a dissolved superparamagnetic iron oxide was injected interstitially. Dynamic, sequential static lymphoscintigraphy and SPECT served as pathfinders. MR imaging was performed 2 h after injection. SPECT, contrast MRI and, if necessary, CT scan data sets were fused and evaluated with special regard to the topographical location of SLNs. The day after injection, nine patients underwent SLN biopsy and, in the presence of SLN metastasis, an elective lymph node dissection. Twenty-five SLNs were localised in the 14 patients examined. A 100% fusion correlation was achieved in all patients. The anatomical sites of SLNs detected during surgery showed 100% agreement with those localised on the multimodal fusion images. SLNs could be excised in 11/14 patients, six of whom had nodal metastasis. Our novel approach of multimodal fusion imaging for targeted SLN management in primary tumours with lymphatic drainage to anatomically difficult regions enables SLN biopsy even in patients with lymphatic drainage to obscure regions. Currently, we are testing its validity in larger patient groups and other tumour entities.

Krokodile Injectors in Ukraine: Fueling the HIV Epidemic?

PubMed

Booth, Robert E; Davis, Jonathan M; Brewster, John T; Lisovska, Oksana; Dvoryak, Sergey

2016-02-01

This study was designed to assess the characteristics of krokodile injectors, a recent phenomenon in Ukraine, and HIV-related risk factors among people who inject drugs (PWID). In three Ukraine cities, Odessa, Donetsk and Nikolayev, 550 PWID were recruited between December 2012 and October 2013 using modified targeted sampling methods. The sample averaged 31 years of age and they had been injecting for over 12 years. Overall, 39 % tested positive for HIV, including 45 % of krokodile injectors. In the past 30 days, 25 % reported injecting krokodile. Those who injected krokodile injected more frequently (p < 0.001) and they injected more often with others (p = 0.005). Despite knowing their HIV status to be positive, krokodile users did not reduce their injection frequency, indeed, they injected as much as 85 % (p = 0.016) more frequently than those who did not know their HIV status or thought they were negative. This behavior was not seen in non-krokodile using PWID. Although only a small sample of knowledgeable HIV positive krokodile users was available (N = 12), this suggests that krokodile users may disregard their HIV status more so than nonkrokodile users. In spite of widespread knowledge of its harmful physical consequences, a growing number of PWID are turning to injecting krokodile in Ukraine. Given the recency of krokodile use the country, the associated higher frequency of injecting, a propensity to inject more often with others, and what could be a unique level of disregard of HIV among krokodile users, HIV incidence could increase in future years.

Micro-CT in situ study of carbonate rock microstructural evolution for geologic CO2 storage

NASA Astrophysics Data System (ADS)

Zheng, Y.; Yang, Y.; Rogowska, M.; Gundlach, C.

2017-09-01

To achieve the 2°C target made in the 2016 Paris Agreement, it is essential to reduce the emission of CO2 into the atmosphere. Carbon Capture and Storage (CCS) has been given increasing importance over the last decade. One of the suggested methods for CCS is to inject CO2 into geologic settings such as the carbonate reservoirs in the North Sea. The final aim of our project is to find out how to control the evolution of petrophysical parameters during CO2 injection using an optimal combination of flow rate, injection pressure and chemical composition of the influent. The first step to achieve this is to find a suitable condition to create a stable 3D space in carbonate rock by injecting liquid to prepare space for the later CO2 injection. Micro-CT imaging is a non-destructive 3D method that can be used to study the property changes of carbonate rocks during and after CO2 injection. The advance in lab source based micro-CT has made it capable of in situ experiments. We used a commercial bench top micro-CT (Zeiss Versa XRM410) to study the microstructure changes of chalk during liquid injection. Flexible temporal CT resolution is essential in this study because that the time scales of coupled physical and chemical processes can be very different. The results validated the feasibility of using a bench top CT system with a pressure cell to monitor the mesoscale multiphase interactions in chalk.

MicroRNA-16 Alleviates Inflammatory Pain by Targeting Ras-Related Protein 23 (RAB23) and Inhibiting p38 MAPK Activation.

PubMed

Chen, Wenjin; Guo, Shengdong; Wang, Shenggang

2016-10-22

BACKGROUND The purpose of our study was to determine the functional role of microRNA (miR)-16 in chronic inflammatory pain and to disclose its underlying molecular mechanism. MATERIAL AND METHODS Inflammatory pain was induced by injection of complete Freund's adjuvant (CFA) to Wistar rats. The pWPXL-miR-16, PcDNA3.1- Ras-related protein (RAB23), and/or SB203580 were delivered intrathecally to the rats. Behavioral tests were detected at 0 h, 4 h, 1 d, 4 d, 7 d, and 14 d after CFA injection. After behavioral tests, L4-L6 dorsal spinal cord were obtained and the levels of miR-16, RAB23, and phosphorylation of p38 (p-p38) were evaluated by quantitative real-time PCR (qRT-PCR). In addition, luciferase reporter assay was performed to explore whether RAB23 was a target of miR-16, and qRT-PCR and Western blotting were used to confirm the regulation between RAB23 and miR-16. RESULTS The level of miR-16 was significantly decreased in the CFA-induced inflammatory pain. Intrathecal injection of miR-16 alleviates pain response and raised pain threshold. The level of RAB23 was significantly increased in the pain model, and intrathecal injection of RAB23 aggravated pain response. Luciferase reporter assay confirmed that RAB23 was a direct target of miR-16, and RAB23 was negatively regulated by miR-16. In addition, we found that simultaneous administration of SB203580 and miR-16 further alleviates pain response compared to only administration of miR-16. CONCLUSIONS Our findings suggest that miR-16 relieves chronic inflammatory pain by targeting RAB23 and inhibiting p38 MAPK activation.

Intra-articular injection of a nutritive mixture solution protects articular cartilage from osteoarthritic progression induced by anterior cruciate ligament transection in mature rabbits: a randomized controlled trial

PubMed Central

Park, Yoo-Sin; Lim, Si-Woong; Lee, Il-Hoon; Lee, Tae-Jin; Kim, Jong-Sung; Han, Jin Soo

2007-01-01

Osteoarthritis (OA) is a degenerative disease that disrupts the collagenous matrix of articular cartilage and is difficult to cure because articular cartilage is a nonvascular tissue. Treatment of OA has targeted macromolecular substitutes for cartilage components, such as hyaluronic acid or genetically engineered materials. However, the goal of the present study was to examine whether intra-articular injection of the elementary nutrients restores the matrix of arthritic knee joints in mature animals. A nutritive mixture solution (NMS) was composed of elementary nutrients such as glucose or dextrose, amino acids and ascorbic acid. It was administered five times (at weeks 6, 8, 10, 13 and 16) into the unilateral anterior cruciate ligament transected knee joints of mature New Zealand White rabbits, and the effect of NMS injection was compared with that of normal saline. OA progression was histopathologically evaluated by haematoxylin and eosin staining, by the Mankin grading method and by scanning electron microscopy at week 19. NMS injection decreased progressive erosion of articular cartilage overall compared with injection of normal saline (P < 0.01), and nms joints exhibited no differences relative to normal cartilage that had not undergone transection of the anterior cruciate ligament, as assessed using the mankin grading method. Haematoxylin and eosin staining and scanning electron microscopy findings also indicated that nms injection, in constrast to normal saline injection, restored the cartilage matrix, which is known to be composed of a collagen and proteoglycan network. thus, nms injection is a potent treatment that significantly retards oa progression, which in turn prevents progressive destruction of joints and functional loss in mature animals. PMID:17257416

Gene Delivery to Postnatal Rat Brain by Non-ventricular Plasmid Injection and Electroporation

PubMed Central

Molotkov, Dmitry A.; Yukin, Alexey Y.; Afzalov, Ramil A.; Khiroug, Leonard S.

2010-01-01

Creation of transgenic animals is a standard approach in studying functions of a gene of interest in vivo. However, many knockout or transgenic animals are not viable in those cases where the modified gene is expressed or deleted in the whole organism. Moreover, a variety of compensatory mechanisms often make it difficult to interpret the results. The compensatory effects can be alleviated by either timing the gene expression or limiting the amount of transfected cells. The method of postnatal non-ventricular microinjection and in vivo electroporation allows targeted delivery of genes, siRNA or dye molecules directly to a small region of interest in the newborn rodent brain. In contrast to conventional ventricular injection technique, this method allows transfection of non-migratory cell types. Animals transfected by means of the method described here can be used, for example, for two-photon in vivo imaging or in electrophysiological experiments on acute brain slices. PMID:20972387

Minimally invasive convection-enhanced delivery of biologics into dorsal root ganglia: validation in the pig model and prospective modeling in humans. Technical note.

PubMed

Pleticha, Josef; Maus, Timothy P; Christner, Jodie A; Marsh, Michael P; Lee, Kendall H; Hooten, W Michael; Beutler, Andreas S

2014-10-01

Dorsal root ganglia (DRG) are critical anatomical structures involved in nociception. Intraganglionic (IG) drug delivery is therefore an important route of administration for novel analgesic therapies. Although IG injection in large animal models is highly desirable for preclinical biodistribution and toxicology studies of new drugs, no method to deliver pharmaceutical agents into the DRG has been reported in any large species. The present study describes a minimally invasive technique of IG agent delivery in domestic swine, one of the most common large animal models. The technique utilizes CT guidance for DRG targeting and a custom-made injection assembly for convection enhanced delivery (CED) of therapeutic agents directly into DRG parenchyma. The DRG were initially visualized by CT myelography to determine the optimal access route to the DRG. The subsequent IG injection consisted of 3 steps. First, a commercially available guide needle was advanced to a position dorsolateral to the DRG, and the dural root sleeve was punctured, leaving the guide needle contiguous with, but not penetrating, the DRG. Second, the custom-made stepped stylet was inserted through the guide needle into the DRG parenchyma. Third, the stepped stylet was replaced by the custom-made stepped needle, which was used for the IG CED. Initial dye injections performed in pig cadavers confirmed the accuracy of DRG targeting under CT guidance. Intraganglionic administration of adeno-associated virus in vivo resulted in a unilateral transduction of the injected DRG, with 33.5% DRG neurons transduced. Transgene expression was also found in the dorsal root entry zones at the corresponding spinal levels. The results thereby confirm the efficacy of CED by the stepped needle and a selectivity of DRG targeting. Imaging-based modeling of the procedure in humans suggests that IG CED may be translatable to the clinical setting.

A novel immunization method to induce cytotoxic T-lymphocyte responses (CTL) against plasmid-encoded herpes simplex virus type-1 glycoprotein D.

PubMed

Cruz, P E; Khalil, P L; Dryden, T D; Chiou, H C; Fink, P S; Berberich, S J; Bigley, N J

1999-03-05

DNA molecules complexed with an asialoglycoprotein-polycation conjugate, consisting of asialoorosomucoid (ASOR) coupled to poly-L-lysine, can enter hepatocytes which bear receptors for ASOR. We used this receptor-mediated DNA delivery system to deliver plasmid DNA encoding glycoprotein D (gD) of herpes simplex virus type 1 to ASOR-positive cells. Maximum expression of gD protein was seen at 3 days after injection of this preparation in approximately 13% of cells from BALB/c mice [hepatocytes from mice injected intravenously (i.v.) or peritoneal exudate cells from mice injected intraperitoneally (i.p.)]. In comparison with mice injected with either the plasmid vector alone or the gD-containing plasmid uncomplexed to ASOR, mice immunized with gD-containing plasmid complexed with ASOR-poly-L-lysine induced marked antigen-specific CTL responses. BALB/c mice immunized with gD-DNA developed a T-cell-mediated CTL response against target cells expressing gD and MHC class II glycoproteins, but not against cells expressing only gD and MHC class I molecules. In C3H mice, gD-DNA induced a T-cell-mediated CTL response against target cells expressing gD and class I MHC molecules. Serum anti-gD antibody in low titers were produced in both strains of mice. DNA complexed with ASOR-poly-L-lysine induced CTL responses in mice.

Renal Sympathetic Denervation by CT-scan-Guided Periarterial Ethanol Injection in Sheep

DOE Office of Scientific and Technical Information (OSTI.GOV)

Firouznia, Kavous, E-mail: k-firouznia@yahoo.com; Hosseininasab, Sayed jaber, E-mail: dr.hosseininasab@gmail.com; Amanpour, Saeid, E-mail: saeidamanpour@yahoo.com

BackgroundRenal nerves are a recent target in the treatment of hypertension. Renal sympathetic denervation (RSD) is currently performed using catheter-based radiofrequency ablation (RFA) and because this method has limitations, percutaneous magnetic resonance (MR)-guided periarterial ethanol injection is a suggested alternative. However, few studies have been conducted on the effectiveness of percutaneous ethanol injection for RSD.AimTo evaluate the feasibility, efficacy, and complications of computed tomography (CT)-guided periarterial ethanol injection.MethodsEthanol (10 ml, 99.6 %) was injected around the right renal artery in six sheep under CT guidance with the left kidney serving as a control. Before and after the intervention, the sheep underwent MRmore » imaging studies and the serum creatinine level was measured. One month after the intervention, the sheep were euthanized and norepinephrine (NE) concentration in the renal parenchyma was measured to evaluate the efficacy of the procedure. The treated tissues were also examined histopathologically to evaluate vascular, parenchymal, and neural injury.ResultsThe right kidney parenchymal NE concentration decreased significantly compared with the left kidney after intervention (average reduction: 40 %, P = 0.0016). Histologic examination revealed apparent denervation with no other vascular or parenchymal injuries observed in the histological and imaging studies.ConclusionEffective and feasible RSD was achieved using CT-guided periarterial ethanol injection. This technique may be a potential alternative to catheter-based RFA in the treatment of hypertension.« less

Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule-1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury.

PubMed

Zou, Xiangyu; Jiang, Kai; Puranik, Amrutesh S; Jordan, Kyra L; Tang, Hui; Zhu, Xiangyang; Lerman, Lilach O

2018-05-01

Mesenchymal stem cells (MSC) have been experimentally used for kidney repair, but modest retention limits their efficacy. Cell-surface coating allows modulating MSC homing and interaction with target cells. We coated mouse adipose tissue-derived MSC with antibodies directed against kidney injury molecule-1 (ab-KIM1), which is upregulated in injured kidneys, and tested the hypothesis that this would enhance their therapeutic effects in ischemic kidney injury. Untreated MSC, ab-KIM1-coated MSC (KIM-MSC), or vehicle, were injected systemically into the carotid artery of 2-kidneys, 1-clip mice 2 weeks after surgery. MSC retention in different organs was explored 24 hours, 48 hours, or 2 weeks after injection. Renal volume, perfusion, and oxygenation were studied 2 weeks after injection using magnetic resonance imaging in vivo, and renal inflammation, apoptosis, capillary density, and fibrosis ex vivo. The ab-KIM1 coating had little effect on MSC viability or proliferation. The stenotic kidney showed upregulated KIM1 expression, selective homing, and greater retention of KIM-MSC compared to untreated MSC and compared to other organs. KIM-MSC-injected mice improved renal perfusion and capillary density, and attenuated oxidative damage, apoptosis, and fibrosis compared to mice treated with vehicle or with native MSC. In conclusion, MSC coating with ab-KIM1 increased their retention in the ischemic kidney and enhanced their therapeutic efficacy. This novel method may be useful to selectively target injured kidneys, and supports further development of strategies to enhance cell-based treatment of ischemic kidney injury. Stem Cells Translational Medicine 2018;7:394-403. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule‐1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury

PubMed Central

Zou, Xiangyu; Jiang, Kai; Puranik, Amrutesh S.; Jordan, Kyra L.; Tang, Hui

2018-01-01

Abstract Mesenchymal stem cells (MSC) have been experimentally used for kidney repair, but modest retention limits their efficacy. Cell‐surface coating allows modulating MSC homing and interaction with target cells. We coated mouse adipose tissue‐derived MSC with antibodies directed against kidney injury molecule‐1 (ab‐KIM1), which is upregulated in injured kidneys, and tested the hypothesis that this would enhance their therapeutic effects in ischemic kidney injury. Untreated MSC, ab‐KIM1‐coated MSC (KIM‐MSC), or vehicle, were injected systemically into the carotid artery of 2‐kidneys, 1‐clip mice 2 weeks after surgery. MSC retention in different organs was explored 24 hours, 48 hours, or 2 weeks after injection. Renal volume, perfusion, and oxygenation were studied 2 weeks after injection using magnetic resonance imaging in vivo, and renal inflammation, apoptosis, capillary density, and fibrosis ex vivo. The ab‐KIM1 coating had little effect on MSC viability or proliferation. The stenotic kidney showed upregulated KIM1 expression, selective homing, and greater retention of KIM‐MSC compared to untreated MSC and compared to other organs. KIM‐MSC‐injected mice improved renal perfusion and capillary density, and attenuated oxidative damage, apoptosis, and fibrosis compared to mice treated with vehicle or with native MSC. In conclusion, MSC coating with ab‐KIM1 increased their retention in the ischemic kidney and enhanced their therapeutic efficacy. This novel method may be useful to selectively target injured kidneys, and supports further development of strategies to enhance cell‐based treatment of ischemic kidney injury. Stem Cells Translational Medicine 2018;7:394–403 PMID:29446551

Improving Injectable Medicines Prescription in Outpatient Services: A Path Towards Rational Use of Medicines in Iran

PubMed Central

Bairami, Firoozeh; Soleymani, Fatemeh; Rashidian, Arash

2016-01-01

Injection is one of the most common medical procedures in the health sector. Annually up to 16 billion injections are prescribed in low- and middle-income countries (LMICs), many of them are not necessary for the patients, increase the healthcare costs and may result in side effects. Currently over 40% of outpatient prescriptions in Iran contain at least one injectable medicine. To address the issue, a working group was established (August 2014 to April 2015) to provide a comprehensive policy brief to be used by national decision-makers. This report is the extract of methods that were followed and the main policy options for improving injectable medicines prescribing in outpatient services. Thirty-three potential policy options were developed focusing on different stakeholders. The panel reached consensus on seven policy options, noting effectiveness, cost, durability, and feasibility of each policy. The recommended policy options are targeted at patients and public (2 policies), insurers (2), physicians (1), pharmacies (1), and the Ministry of Health and Medical Education (MoHME) (1). PMID:27239881

Development of 177Lu-phytate Complex for Radiosynovectomy

PubMed Central

Yousefnia, Hassan; Jalilian, Amir Reza; Bahrami-Samani, Ali; Mazidi, Mohammad; Ghannadi Maragheh, Mohammad; Abbasi-Davani, Fereydoun

2013-01-01

Objective(s): In this work a new possible agent for radiosynovectomy has been targeted for articular pain palliation. Materials and Methods: Lu-177 of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu2O3 sample with thermal neutron flux of 4 × 1013 n.cm-2.s-1. The product was converted into chloride form which was further used for labeling of 177Lu-phytate complex and checked using ITLC (MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase). The complex stability and viscosity were checked in the final solution up to seven days. The prepared complex solution (100 µCi/100 µl) was injected intra-articularly to male rat knee joint. Leakage of radioactivity from injection site and its distribution in organs were investigated up to seven days. Results: The complex was successfully prepared with high radiochemical purity (>99.9 %). Approximately, the whole injected dose has remained in injection site seven days after injection. Conclusion: The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology. PMID:23826493

Tattoo Delivery of a Semliki Forest Virus-Based Vaccine Encoding Human Papillomavirus E6 and E7.

PubMed

van de Wall, Stephanie; Walczak, Mateusz; van Rooij, Nienke; Hoogeboom, Baukje-Nynke; Meijerhof, Tjarko; Nijman, Hans W; Daemen, Toos

2015-03-24

The skin is an attractive organ for immunization because of the presence of antigen-presenting cells. Intradermal delivery via tattooing has demonstrated superior vaccine immunogenicity of DNA vaccines in comparison to conventional delivery methods. In this study, we explored the efficacy of tattoo injection of a tumor vaccine based on recombinant Semliki Forest virus replicon particles (rSFV) targeting human papillomavirus (HPV). Tattoo injection of rSFV particles resulted in antigen expression in both the skin and draining lymph nodes. In comparison with intramuscular injection, the overall antigen expression determined at the site of administration and draining lymph nodes was 10-fold lower upon tattoo injection. Delivery of SFV particles encoding the E6 and E7 antigens of human papillomavirus type 16 (SFVeE6,7) via tattooing resulted in HPV-specific cytotoxic T cells and in vivo therapeutic antitumor response. Strikingly, despite the observed lower overall transgene expression, SFVeE6,7 delivered via tattoo injection resulted in higher or equal levels of immune responses as compared to intramuscular injection. The intrinsic immunogenic potential of tattooing provides a benefit for immunotherapy based on an alphavirus.

Tattoo Delivery of a Semliki Forest Virus-Based Vaccine Encoding Human Papillomavirus E6 and E7

PubMed Central

van de Wall, Stephanie; Walczak, Mateusz; van Rooij, Nienke; Hoogeboom, Baukje-Nynke; Meijerhof, Tjarko; Nijman, Hans W.; Daemen, Toos

2015-01-01

The skin is an attractive organ for immunization because of the presence of antigen-presenting cells. Intradermal delivery via tattooing has demonstrated superior vaccine immunogenicity of DNA vaccines in comparison to conventional delivery methods. In this study, we explored the efficacy of tattoo injection of a tumor vaccine based on recombinant Semliki Forest virus replicon particles (rSFV) targeting human papillomavirus (HPV). Tattoo injection of rSFV particles resulted in antigen expression in both the skin and draining lymph nodes. In comparison with intramuscular injection, the overall antigen expression determined at the site of administration and draining lymph nodes was 10-fold lower upon tattoo injection. Delivery of SFV particles encoding the E6 and E7 antigens of human papillomavirus type 16 (SFVeE6,7) via tattooing resulted in HPV-specific cytotoxic T cells and in vivo therapeutic antitumor response. Strikingly, despite the observed lower overall transgene expression, SFVeE6,7 delivered via tattoo injection resulted in higher or equal levels of immune responses as compared to intramuscular injection. The intrinsic immunogenic potential of tattooing provides a benefit for immunotherapy based on an alphavirus. PMID:26343186

A method for improving the accuracy of stereotaxic procedures in monkeys using implanted fiducial markers in CT scans that also serve as anchor points in a stereotaxic frame.

PubMed

Risher, D W; Zhang, X; Kostarczyk, E; Gokin, A P; Honda, C N; Giesler, G J

1997-04-25

We developed a relatively inexpensive method for stereotaxic placement of electrodes or needles in the brains of monkeys. Steel balls were affixed to the skulls of monkeys. These balls served as fiducial markers and were also used as points at which the monkey's skull was held in a modified stereotaxic apparatus. Computed tomography (CT) was used to establish the location of an injection target with respect to the fiducial markers. A computer program related the CT coordinates to stereotaxic coordinates. These were used to direct an electrode marker toward a target in the hypothalamus. With the marker left in place, the monkey was removed from the stereotaxic frame and a second CT scan was performed. Corrections for errors in marker placement were made and retrograde tracers were injected. This procedure was found to be more accurate and reliable than conventional stereotaxic procedures. The accuracy and repeatability of the technique were also established using a phantom model of a monkey's skull. Two important advantages of this method are that animals can be repeatedly placed into the stereotaxic frame in precisely the same position and that there are many opportunities during the procedure to check for and correct errors.

(+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism

PubMed Central

Zhao, Jing; Mysona, Barbara A.; Qureshi, Azam; Kim, Lily; Fields, Taylor; Gonsalvez, Graydon B.; Smith, Sylvia B.; Bollinger, Kathryn E.

2016-01-01

Purpose To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)-pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. Methods Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1−/− (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)-pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. Results N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. Conclusions Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases. PMID:26868747

Peripheral nerve catheters and local anesthetic infiltration in perioperative analgesia.

PubMed

Merritt, Christopher K; Mariano, Edward R; Kaye, Alan David; Lissauer, Jonathan; Mancuso, Kenneth; Prabhakar, Amit; Urman, Richard D

2014-03-01

Peripheral nerve catheters (PNCs) and local infiltration analgesia (LIA) represent valuable options for controlling perioperative pain. PNCs have been increasingly utilized to provide both surgical anesthesia and prolonged postoperative analgesia for a wide variety of procedures. PNCs can be more technically challenging to place than typical single-injection nerve blocks (SINB), and familiarity with the indications, contraindications, relevant anatomy, and appropriate technical skills is a prerequisite for the placement of any PNC. PNCs include risks of peripheral nerve injury, damage to adjacent anatomic structures, local anesthetic toxicity, intravascular injection, risks associated with motor block, risks of unnoticed injury to the insensate limb, and risks of sedation associated with PNC placement. In addition to these common risks, there are specific risks unique to each PNC insertion site. LIA strategies have emerged that seek to provide the benefit of targeted local anesthesia while minimizing collateral motor block and increasing the applicability of durable local anesthesia beyond the extremities. LIA involves the injection and/or infusion of a local anesthetic near the site of surgical incision to provide targeted analgesia. A wide variety of techniques have been described, including single-injection intraoperative wound infiltration, indwelling wound infusion catheters, and the recent high-volume LIA technique associated with joint replacement surgery. The efficacy of these techniques varies depending on specific procedures and anatomic locations. The recent incorporation of ultra-long-acting liposomal bupivacaine preparations has the potential to dramatically increase the utility of single-injection LIA. LIA represents a promising yet under-investigated method of postoperative pain control. Copyright © 2014 Elsevier Ltd. All rights reserved.

MRI - 3D Ultrasound - X-ray Image Fusion with Electromagnetic Tracking for Transendocardial Therapeutic Injections: In-vitro Validation and In-vivo Feasibility

PubMed Central

Hatt, Charles R.; Jain, Ameet K.; Parthasarathy, Vijay; Lang, Andrew; Raval, Amish N.

2014-01-01

Myocardial infarction (MI) is one of the leading causes of death in the world. Small animal studies have shown that stem-cell therapy offers dramatic functional improvement post-MI. An endomyocardial catheter injection approach to therapeutic agent delivery has been proposed to improve efficacy through increased cell retention. Accurate targeting is critical for reaching areas of greatest therapeutic potential while avoiding a life-threatening myocardial perforation. Multimodal image fusion has been proposed as a way to improve these procedures by augmenting traditional intra-operative imaging modalities with high resolution pre-procedural images. Previous approaches have suffered from a lack of real-time tissue imaging and dependence on X-ray imaging to track devices, leading to increased ionizing radiation dose. In this paper, we present a new image fusion system for catheter-based targeted delivery of therapeutic agents. The system registers real-time 3D echocardiography, magnetic resonance, X-ray, and electromagnetic sensor tracking within a single flexible framework. All system calibrations and registrations were validated and found to have target registration errors less than 5 mm in the worst case. Injection accuracy was validated in a motion enabled cardiac injection phantom, where targeting accuracy ranged from 0.57 to 3.81 mm. Clinical feasibility was demonstrated with in-vivo swine experiments, where injections were successfully made into targeted regions of the heart. PMID:23561056

An injection and mixing element for delivery and monitoring of inhaled nitric oxide.

PubMed

Martin, Andrew R; Jackson, Chris; Fromont, Samuel; Pont, Chloe; Katz, Ira M; Caillobotte, Georges

2016-08-30

Inhaled nitric oxide (NO) is a selective pulmonary vasodilator used primarily in the critical care setting for patients concurrently supported by invasive or noninvasive positive pressure ventilation. NO delivery devices interface with ventilator breathing circuits to inject NO in proportion with the flow of air/oxygen through the circuit, in order to maintain a constant, target concentration of inhaled NO. In the present article, a NO injection and mixing element is presented. The device borrows from the design of static elements to promote rapid mixing of injected NO-containing gas with breathing circuit gases. Bench experiments are reported to demonstrate the improved mixing afforded by the injection and mixing element, as compared with conventional breathing circuit adapters, for NO injection into breathing circuits. Computational fluid dynamics simulations are also presented to illustrate mixing patterns and nitrogen dioxide production within the element. Over the range of air flow rates and target NO concentrations investigated, mixing length, defined as the downstream distance required for NO concentration to reach within ±5 % of the target concentration, was as high as 47 cm for the conventional breathing circuit adapters, but did not exceed 7.8 cm for the injection and mixing element. The injection and mixing element has potential to improve ease of use, compatibility and safety of inhaled NO administration with mechanical ventilators and gas delivery devices.

Evaluation of an online injecting drug use stigma intervention targeted at health providers in New South Wales, Australia

PubMed Central

Brener, Loren; Cama, Elena; Hull, Peter; Treloar, Carla

2017-01-01

People who inject drugs are highly stigmatised. Discriminatory experiences are commonly reported, particularly in health care settings. This article evaluates an online stigma reduction training module targeting health providers working with people who inject drugs. A total of 139 participants completed a pre- and post-survey including attitude items and items depicting hypothetical scenarios and concerns around client behaviours. Participants’ attitudes towards people who inject drugs were more positive and they showed less concerns about client behaviours after completing the online training module. Findings highlight the benefits of online training in reducing discriminatory attitudes towards people who inject drugs and improving confidence in working with this client group. PMID:28567299

Intra-Arterial Delivery of AAV Vectors to the Mouse Brain After Mannitol Mediated Blood Brain Barrier Disruption

PubMed Central

Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Crystal, Ronald G.; Gobin, Y. Pierre; Ballon, Douglas J.

2014-01-01

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration. PMID:25270115

Simultaneous Treatment with Subcutaneous Injection of Golimumab and Intra-articular Injection of Triamcinolone Acetonide (K-Method) in Patients with Rheumatoid Arthritis Undergoing Switching of Biologics: Retrospective Case–Control Study

PubMed Central

Kanbe, Katsuaki; Chiba, Junji; Inoue, Yasuo; Taguchi, Masashi; Yabuki, Akiko; Deguchi, Tomohiko

2016-01-01

BACKGROUND Tight control of severe rheumatoid arthritis (RA) in patients with high disease activity, even when using biologics, is sometimes difficult using a treat-to-target strategy. Switching from one biologic to another is associated with lower efficacy than that in treatment-naive cases. We developed the K-method that involves simultaneous treatment with golimumab and intra-articular joint injection of triamcinolone acetonide (TA) in patients undergoing switching of biologics. We performed this retrospective case–control study to investigate the efficacy of achieving an immediate treatment response using the K-method. METHODS This study involved 20 patients with RA (control group, 10 patients; K-method group, 10 patients). Patients in the control group were switched to golimumab from other biologics without intra-articular injection of TA. The K-method involved injection of 1 mL of TA (40 mg/mL) and 2 mL of 1% lidocaine hydrochloride into swollen or painful joints on the same day as golimumab treatment. A quick response one day after treatment was compared between the two groups according to the disease activity score 28 based on C-reactive protein (DAS28 CRP), clinical disease activity index (CDAI), simplified disease activity index (SDAI), European League Against Rheumatism (EULAR) response, and remission rate. These parameters were investigated for 24 weeks. RESULTS The K-method group showed significant improvements in DAS28 CRP, CDAI, and SDAI at one day, 12 weeks, and 24 weeks compared with the control group. The number of swollen and tender joints and the patient and doctor global visual analog scale scores were also significantly different between the two groups. The remission rates based on DAS28 CRP were 30% at one day, 50% at 12 weeks, and 60% at 24 weeks in the K-method group. The EULAR good/moderate response rates were 80% at one day, 90% at 12 weeks, and 90% at 24 weeks in the K-method group; however, these rates were only 10%, 40%, and 40%, respectively, in the control group. No adverse events occurred in either group. CONCLUSION Simultaneous treatment with biologics and intra-articular injection of TA is useful for cases involving switching of biologics for RA. This strategy is safe and practical for RA treatment. PMID:27081319

[Study on liver targeted drug delivery system of the effective anticancer component from Bolbstemma paniculatum].

PubMed

Sun, Yi-Yi; Ll, Tong-Hui; Tang, Chen-Kang; Zhu, Zi-Ping; Chi, Qun; Hou, Shi-Xiang

2005-06-01

To study the liver targeted drug delivery system of TBMS--the effective anticancer component from Bolbstemma paniculatum, and to discuss the system's function of decreasing toxicity. BCA was used as carrier material. The preparation through overall feedback dynamic techniques. The properties of preparation and toxicology were also technology of nanoparticles was optimized studied. Thenanoparticles' targeting in mice vivo was observed with transmission electron microscopy. The function of decreasing toxicity was researched by the XXTX-2000 automatic quantitative analysis management system. D50 was 0.68 microm. Drug-loading rate and entrapment rate were 37.3% and 88.6% respectively. The release in vitro accorded with Weibull equation. The reaching release balance time and the t 1/2 extended 26 times and 19 times respectively comparing with injection. Nanoparticles mainly distributed in liver tissue. Their toxicity to lung and liver was evidently lower than injection. Nanoparticles' LD50 exceeded injection's by 13.5% and their stimulus was much lower than injection. The TBMS can be targeted to liver by liver targeted drug delivery system. At the same time, the problem about the toxicity hindering clinical application could be solved, which lays the foundation for the further studies on TBMS.

Fish egg injection as an alternative exposure route for early life stage toxicity studies: Description of two unique methods: Chapter 4

USGS Publications Warehouse

Walker, Mary K.; Zabel, Erik W.; Akerman, Gun; Balk, Lennart; Wright, Peggy J.; Tillitt, Donald E.

1996-01-01

In the environment, lipophilic contaminants such as halogenated aromatic hydrocarbons (HAHs, e.g., polychlorinated biphenyls, PCBs) and polycyclic aromatic hydrocarbons (PAHs, e.g., benzo[a]pyrene) readily bioaccumulate in fish, and the bioaccumulation of these lipophilic chemicals by adult fish may have significant consequences on the development and survival of their offspring. Halogenated and polycyclic aromatic hydrocarbons translocate from adult female body stores into eggs during oocyte maturation, and early life stages of fish are often more sensitive than adults to the toxicity of these chemicals. Thus, the presence of persistent, bioaccumulative contaminants in the environment may pose a risk to fish early life stage survival and ultimately reduce recruitment into the adult population.Typically, standard early life stage toxicity studies exposed embryos, larvae, and juveniles to graded concentrations of waterborne toxicants, and dose-response relationships are based on the concentrations of chemicals in the water. However, use of waterborne exposure to assess the toxicity of persistent, bioaccumulative contaminants, such as HAHs and PAHs, has two significant drawbacks. First, uptake of hydrophobic chemicals, such as HAHs and PAHs, into the developing embryo from water is not a significant route of exposure in the environment since concentrations of these chemicals freely dissolved in water are extremely low. Rather, maternal deposition into developing oocytes is the most significant source of these chemicals to the embryo. Second, the dose received by the target tissue, in this case the developing embryo, is the most accurate predictor of the toxic response, and since extrapolation from water concentrations of the chemical to egg concentrations is required, the exact dose received by the embryo can only be estimated, often with large uncertainty. Due to these drawbacks, it is important to develop an alternative exposure method that will directly expose the developing embryo without the need to chronically expose adult fish with subsequent natural deposition of hydrophobic chemicals into the oocytes. Fish egg injection provides this exposure route. Embryos are exposed directly after fertilization with known doses of contaminants, the dose is delivered prior to critical developmental events, and extrapolation of the dose received by the embryo is not needed.We have developed two unique fish egg injection methods as alternative routes of exposure for fish early life stage toxicity studies of lipophilic environmental contaminants. With either method, individual fish eggs are injected with a known dose of chemical. The first approach, a microinjection method, originally developed to assess the developmental toxicity of HAH congeners to early life stages of salmonids, utilizes micro-syringes, 30- gauge stainless steel injection needles, and micro- to nanoliter injection volume. The second approach, a nano-injection method, utilizes glass capillary micropipettes with 2 to 10 µm tips as injection needles, and nano- to picoliter injection volume, allowing injection of nearly any size of fish egg.Both of these egg injection methods allow an investigator to assess the toxicity of lipophilic environmental contaminants to early life stages of fish in a manner that realistically reflects environmental exposure and allows accurate quantitation of the dose to the developing embryo. These injection techniques, however, are not limited to use with only lipophilic chemicals. Since the developmental toxicity of many environmental contaminants ultimately depends on the dose received by the embryo, these egg injection methods could serve as a realistic exposure route in many fish early life stage toxicity studies.

In Vivo Kinetics of Mesenchymal Stem Cells Transplanted into the Knee Joint in a Rat Model Using a Novel Magnetic Method of Localization.

PubMed

Ikuta, Yasunari; Kamei, Naosuke; Ishikawa, Masakazu; Adachi, Nobuo; Ochi, Mitsuo

2015-10-01

We have developed a magnetic system for targeting cells in minimally invasive cell transplantation. Magnetically labeled MSCs (m-MSCs) with nanoscale iron particles can be guided into the desired region by magnetic force from an extracorporeal device. We reported that magnetic targeting of m-MSCs enhances cartilage repair in a mini-pig model. However, the detailed kinetics of these magnetically targeted m-MSCs remain unknown. For clinical use, this aspect should be clarified from a safety standpoint. We therefore investigated the spatial and temporal distribution of the fluorescently-labeled m-MSCs transplanted into the knee joint using in vivo fluorescence combined with three-dimensional computed tomographic imaging in a rat model. Although the intraarticularly injected m-MSCs were spread throughout the joint cavity in the absence of magnetic force, the magnetic force caused the injected m-MSCs to accumulate around the chondral lesion. Further examinations including ex vivo imaging, histological assessments and reverse transcription polymerase chain reaction revealed that transplanted MSCs were not present in any major organs after intraarticular administration, regardless of magnetic targeting. Our data suggest that m-MSCs can be accumulated efficiently into a chondral lesion using our magnetic targeting system, while none of the intraarticularly transplanted MSCs migrate to other major organs. © 2015 Wiley Periodicals, Inc.

Folate receptor mediated in vivo targeted delivery of human serum albumin coated manganese ferrite magnetic nanoparticles to cancer cells

NASA Astrophysics Data System (ADS)

Zaidan, A.; Ilhami, F.; Fahmi, M. Z.; Purwanto, B.; Kharisma, R. Z.

2017-05-01

Manganese ferrite nanoparticles (MnFe2O4) have received increasing attention due to their remarkable magnetic properties and have been used for various biomedical applications. They have potential applications in magnetic resonance imaging and hyperthermia for cancer. Both novel applications require a delivery system that will allow nanoparticle to move easily and localization of nanoparticle to the target tissue. In our work, we developed human serum albumin coated manganese ferrite magnetic nanoparticles (HSA-MF NPs). The nanoparticles were prepared using solvothermal method and modified with folic acid for targeted delivery. Structure and morphology of manganese ferrite nanoparticle were characterized by X-ray diffraction (XRD) pattern and transmission electron microscopy (TEM). The size of folic acid conjugated HSA-MF NPs (HSA-MF-FA NPs) were studied by dynamic light scattering (DLS). In the in vivo study, we used benzopyrene-induced cancer in mice. We successfully delivered HSA-MF-FA NPs through intravenous tail injection after induction of the tumour. We found that 54% of initial HSA-MF-FA NPs which previously injected localize in the target tissue. While obtained p-value from independent T-test is 0.013 which shows that there is a difference between the control group (HSA-MF NPs) and the treated group (HSA-MF-FA NPs)

The syringe gap: an assessment of sterile syringe need and acquisition among syringe exchange program participants in New York City

PubMed Central

Heller, Daliah I; Paone, Denise; Siegler, Anne; Karpati, Adam

2009-01-01

Background Programmatic data from New York City syringe exchange programs suggest that many clients visit the programs infrequently and take few syringes per transaction, while separate survey data from individuals using these programs indicate that frequent injecting – at least daily – is common. Together, these data suggest a possible "syringe gap" between the number of injections performed by users and the number of syringes they are receiving from programs for those injections. Methods We surveyed a convenience sample of 478 injecting drug users in New York City at syringe exchange programs to determine whether program syringe coverage was adequate to support safer injecting practices in this group. Results Respondents reported injecting a median of 60 times per month, visiting the syringe exchange program a median of 4 times per month, and obtaining a median of 10 syringes per transaction; more than one in four reported reusing syringes. Fifty-four percent of participants reported receiving fewer syringes than their number of injections per month. Receiving an inadequate number of syringes was more frequently reported by younger and homeless injectors, and by those who reported public injecting in the past month. Conclusion To improve syringe coverage and reduce syringe sharing, programs should target younger and homeless drug users, adopt non-restrictive syringe uptake policies, and establish better relationships with law enforcement and homeless services. The potential for safe injecting facilities should be explored, to address the prevalence of public injecting and resolve the 'syringe gap' for injecting drug users. PMID:19138414

Assessing spatial uncertainty in reservoir characterization for carbon sequestration planning using public well-log data: A case study

USGS Publications Warehouse

Venteris, E.R.; Carter, K.M.

2009-01-01

Mapping and characterization of potential geologic reservoirs are key components in planning carbon dioxide (CO2) injection projects. The geometry of target and confining layers is vital to ensure that the injected CO2 remains in a supercritical state and is confined to the target layer. Also, maps of injection volume (porosity) are necessary to estimate sequestration capacity at undrilled locations. Our study uses publicly filed geophysical logs and geostatistical modeling methods to investigate the reliability of spatial prediction for oil and gas plays in the Medina Group (sandstone and shale facies) in northwestern Pennsylvania. Specifically, the modeling focused on two targets: the Grimsby Formation and Whirlpool Sandstone. For each layer, thousands of data points were available to model structure and thickness but only hundreds were available to support volumetric modeling because of the rarity of density-porosity logs in the public records. Geostatistical analysis based on this data resulted in accurate structure models, less accurate isopach models, and inconsistent models of pore volume. Of the two layers studied, only the Whirlpool Sandstone data provided for a useful spatial model of pore volume. Where reliable models for spatial prediction are absent, the best predictor available for unsampled locations is the mean value of the data, and potential sequestration sites should be planned as close as possible to existing wells with volumetric data. ?? 2009. The American Association of Petroleum Geologists/Division of Environmental Geosciences. All rights reserved.

New injectors and the social context of injection initiation

PubMed Central

Harocopos, Alex; Goldsamt, Lloyd A.; Kobrak, Paul; Jost, John J.; Clatts, Michael C.

2009-01-01

Background Preventing the onset of injecting drug use is an important public health objective yet there is little understanding of the process that leads to injection initiation. This paper draws extensively on narrative data to describe how injection initiation is influenced by social environment. We examine how watching other people inject can habitualise non-injectors to administering drugs with a needle and consider the process by which the stigma of injecting is replaced with curiosity. Method In-depth interviews (n=54) were conducted as part of a two-year longitudinal study examining the behaviours of new injecting drug users. Results Among our sample, injection initiation was the result of a dynamic process during which administering drugs with a needle became acceptable or even appealing. Most often, this occurred as a result of spending time with current injectors in a social context and the majority of this study’s participants were given their first shot by a friend or sexual partner. Initiates could be tenacious in their efforts to acquire an injection trainer and findings suggest that once injecting had been introduced to a drug-using network, it was likely to spread throughout the group. Conclusion Injection initiation should be viewed as a communicable process. New injectors are unlikely to have experienced the negative effects of injecting and may facilitate the initiation of their drug-using friends. Prevention messages should therefore aim to find innovative ways of targeting beginning injectors and present a realistic appraisal of the long-term consequences of injecting. Interventionists should also work with current injectors to develop strategies to refuse requests from non-injectors for their help to initiate. PMID:18790623

In Situ NAPL Modification for Contaminant Source-Zone Passivation, Mass Flux Reduction, and Remediation

NASA Astrophysics Data System (ADS)

Mateas, D. J.; Tick, G.; Carroll, K. C.

2016-12-01

A remediation method was developed to reduce the aqueous solubility and mass-flux of target NAPL contaminants through the in-situ creation of a NAPL mixture source-zone. This method was tested in the laboratory using equilibrium batch tests and two-dimensional flow-cell experiments. The creation of two different NAPL mixture source zones were tested in which 1) volumes of relatively insoluble n-hexadecane (HEX) or vegetable oil (VO) were injected into a trichloroethene (TCE) contaminant source-zone; and 2) pre-determined HEX-TCE and VO-TCE mixture ratio source zones were emplaced into the flow cell prior to water flushing. NAPL-aqueous phase batch tests were conducted prior to the flow-cell experiments to evaluate the effects of various NAPL mixture ratios on equilibrium aqueous-phase concentrations of TCE and toluene (TOL) and to design optimal NAPL (HEX or VO) injection volumes for the flow-cell experiments. Uniform NAPL mixture source-zones were able to quickly decrease contaminant mass-flux, as demonstrated by the emplaced source-zone experiments. The success of the HEX and VO injections to also decrease mass flux was dependent on the ability of these injectants to homogeneously mix with TCE source-zone. Upon injection, both HEX and VO migrated away from the source-zone, to some extent. However, the lack of a steady-state dissolution phase and the inefficient mass-flux-reduction/mass-removal behavior produced after VO injection suggest that VO was more effective than HEX for mixing and partitioning within the source-zone region to form a more homogeneous NAPL mixture with TCE. VO appears to be a promising source-zone injectant-NAPL due to its negligible long-term toxicity and lower mobilization potential.

Ultrasound-guided Interdigital Neuroma Injections: Short-term Clinical Outcomes after a Single Percutaneous Injection—Preliminary Results

PubMed Central

Adler, Ronald S.; Ciavarra, Gina A.; Pavlov, Helene

2006-01-01

Purpose To describe the procedure of ultrasound-guided Morton’s neuroma and recurrent stump neuroma injections and early clinical outcomes after a single injection. Materials and Methods Retrospective review of 44 percutaneous ultrasound-guided neuroma injections in 24 patients who had completed clinical outcomes questionnaires. A 10-point pain scale [scale of 1 (no pain) to 10 (severe pain)] in a 7-day pain log format was distributed to patients at the time percutaneous neuroma injection was performed. Results Neuromas were clearly visualized with sonography as hypoechoic nodules and were distinguishable from other causes of forefoot pain, such as metatarsophalangeal joint synovitis and intermetatarsal bursae. The sizes of the neuromas injected ranged between 4 and 19 mm. Postinjection, all neuromas displayed increased echogenicity and/or the appearance of fluid surrounding it, confirming localization of the therapeutic mixture. We arbitrarily subdivided the pain ratings into symptomatic (greater than 4) and asymptomatic (less than or equal to 4) for statistical analysis. Average pain level pre injection was 5.2 and average pain level was 3.7 at 7 days post single injection, with 62% of the initially symptomatic patients asymptomatic on day 7 (p < 0.000001). Overall, 76% of the total number of neuromas injected once were asymptomatic on day 7. Conclusion Ultrasound can be used to accurately target Morton’s neuromas and, therefore, appropriately direct therapeutic interventions, with good short-term clinical results. PMID:18751769

Risk Factors Associated with Unsafe Injection Practices at the First Injection Episode among Intravenous Drug Users in France: Results from PrimInject, an Internet Survey.

PubMed

Guichard, Anne; Guignard, Romain; Lert, France; Roy, Elise

2015-01-01

Background. New drug use patterns may increase the risk of human immunodeficiency virus and hepatitis infections. In France, new injection patterns among youths with diverse social backgrounds have emerged, which may explain the persistently high rates of hepatitis C virus infection. This study explores factors associated with injection risk behaviours at first injection among users who began injecting in the post-2000 era. Methods. A cross-sectional study was conducted on the Internet from October 2010 to March 2011, through an online questionnaire. Multivariate logistic regression identified the independent correlates of needle sharing and equipment (cooker/cotton filter) sharing. Results. Among the 262 respondents (mean age 25 years), 65% were male. Both risk behaviours were positively associated with initiation before 18 years of age (aOR 3.7 CI 95% 1.3-10.6 and aOR 3.0 CI 95% 1.3-7.0) and being injected by another person (aOR 3.1 CI 95% 1.0-9.9 and aOR 3.0 CI 95% 1.3-7.1). Initiation at a party was an independent correlate of equipment sharing (aOR 2.6 95% CI 1.0-6.8). Results suggest a need for innovative harm reduction programmes targeting a variety of settings and populations, including youths and diverse party scenes. Education of current injectors to protect both themselves and those they might initiate into injection is critically important.

A rapid gas chromatographic injection-port derivatization method for the tandem mass spectrometric determination of patulin and 5-hydroxymethylfurfural in fruit juices.

PubMed

Marsol-Vall, Alexis; Balcells, Mercè; Eras, Jordi; Canela-Garayoa, Ramon

2016-07-01

A novel method consisting of injection-port derivatization coupled to gas chromatography-tandem mass spectrometry is described. The method allows the rapid assessment of 5-hydroxymethylfurfural (HMF) and patulin content in apple and pear derivatives. The chromatographic separation of the compounds was achieved in a short chromatographic run (12.2min) suitable for routine controls of these compounds in the fruit juice industry. The optimal conditions for the injection-port derivatization were at 270°C, 0.5min purge-off, and a 1:2 sample:derivatization reagent ratio (v/v). These conditions represent an important saving in terms of derivatization reagent consumption and sample preparation time. Quality parameters were assessed for the target compounds, giving LOD of 0.7 and 1.6μg/kg and LOQ of 2 and 5μg/kg for patulin and HMF, respectively. These values are below the maximum patulin concentration in food products intended for infants and young children. Repeatability (%RSD n=5) was below 12% for both compounds. In addition, the method linearity ranged between 25 and 1000μg/kg and between 5 and 192μg/kg for HMF and patulin, respectively. Finally, the method was applied to study HMF and patulin content in various fruit juice samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Working group summary report on effects of pulsed operation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gabriel, T.A.; Ni, L.

1996-06-01

In a short pulsed spallation neutron source, extremely high energy ({approx_gt}1 GeV) proton beam pulses are injected into a liquid metal target in a very short period of time ({approximately}1 {mu}sec) at a high repetition rate ({approximately}50 Hertz). The beam energy will be deposited in the target materials (such as mercury or lead) and converted into heat. It causes a sudden temperature rise and resulting pressure wave. This pressure wave travels through the liquid, reaches the steel container wall and may possibly lead to material damage due to induced stress. Almost all participants agreed that the shock problem due tomore » the short pulse operation in the liquid metal target could be serious and could present a challenging problem. It was determined that the following points need to be addressed: (1) equation of state for mercury (2) code validation and benchmark experiments (3) shock effects on the entire target system (4) two phase flow by gas injection. All these investigations should be carried out in the framework of international cooperation. Two small scaled Hg pressure pulse tests are planned at ORNL to provide insight into the pressure wave propagation and thermal shock effects. One experiment will use exploding wires to generate the pulse pressure, the other the electron beam at ORELA. Also PSI, LANL, CERN (ISOLDE facility), INR and IPPE could contribute to the experimental methods for producing shock. The necessary R&D for bubble injection might be performed at PSI, RIGA, ORNL or Ben-Gurion University. All of the above experiments can possibly yield benchmarking data which is absolutely necessary for code validation.« less

EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases

PubMed Central

Urnauer, Sarah; Müller, Andrea M.; Schug, Christina; Schmohl, Kathrin A.; Tutter, Mariella; Schwenk, Nathalie; Rödl, Wolfgang; Morys, Stephan; Ingrisch, Michael; Bertram, Jens; Bartenstein, Peter; Clevert, Dirk-André; Wagner, Ernst; Spitzweg, Christine

2017-01-01

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease. PMID:29190908

Paclitaxel-loaded iron platinum stealth immunomicelles are potent MRI imaging agents that prevent prostate cancer growth in a PSMA-dependent manner

PubMed Central

Taylor, Robert M; Sillerud, Laurel O

2012-01-01

Background and methods: Problems with the clinical management of prostate cancer include the lack of both specific detection and efficient therapeutic intervention. We report the encapsulation of superparamagnetic iron platinum nanoparticles (SIPPs) and paclitaxel in a mixture of polyethyleneglycolated, fluorescent, and biotin-functionalized phospholipids to create multifunctional SIPP-PTX micelles (SPMs) that were conjugated to an antibody against prostate-specific membrane antigen (PSMA) for the specific targeting, magnetic resonance imaging (MRI), and treatment of human prostate cancer xenografts in mice. Results: SPMs were 45.4 ± 24.9 nm in diameter and composed of 160.7 ± 22.9 μg/mL iron, 247.0 ± 33.4 μg/mL platinum, and 702.6 ± 206.0 μg/mL paclitaxel. Drug release measurements showed that, at 37°C, half of the paclitaxel was released in 30.2 hours in serum and two times faster in saline. Binding assays suggested that PSMA-targeted SPMs specifically bound to C4-2 human prostate cancer cells in vitro and released paclitaxel into the cells. In vitro, paclitaxel was 2.2 and 1.6 times more cytotoxic than SPMs to C4-2 cells at 24 and 48 hours of incubation, respectively. After 72 hours of incubation, paclitaxel and SPMs were equally cytotoxic. SPMs had MRI transverse relaxivities of 389 ± 15.5 Hz/mM iron, and SIPP micelles with and without drug caused MRI contrast enhancement in vivo. Conclusion: Only PSMA-targeted SPMs and paclitaxel significantly prevented growth of C4-2 prostate cancer xenografts in nude mice. Furthermore, mice injected with PSMA-targeted SPMs showed significantly more paclitaxel and platinum in tumors, compared with nontargeted SPM-injected and paclitaxel-injected mice. PMID:22915856

In vivo photothermal optical coherence tomography of gold nanorods in the mouse eye (Conference Presentation)

NASA Astrophysics Data System (ADS)

Lapierre-Landry, Maryse; Gordon, Andrew Y.; Penn, John S.; Skala, Melissa C.

2017-02-01

Optical coherence tomography (OCT) has become standard in retinal imaging at the pre-clinical and clinical level by allowing non-invasive, three-dimensional imaging of the tissue structure. However, OCT lacks specificity to contrast agents that could be used for in vivo molecular imaging. We have performed in vivo photothermal optical coherence tomography (PT-OCT) of targeted gold nanorods in the mouse retina after the mice were injected systemically with the contrast agent. To our knowledge, we are the first to perform PT-OCT in the eye and image targeted gold nanorods with this technology. As a model of age-related wet macular degeneration, lesions were induced by laser photocoagulation in each mouse retina (n=12 eyes). Untargeted and targeted (anti-mouse CD102 antibody, labeling neovasculature) gold nanorods (peak absorption λ=750nm) were injected intravenously by tail-vein injection five days after lesion induction, and imaged the same day with PT-OCT. Our instrument is a spectral domain OCT system (λ=860nm) with a Titanium:Sapphire laser (λ=750nm) added to the beam path using a 50:50 coupler to heat the gold nanorods. We acquired PT-OCT volumes of one lesion per mouse eye. There was a significant increase in photothermal intensity per unit area of the lesion in the targeted gold nanorods group versus the saline control group and the untargeted gold nanorods group. This experiment demonstrates the feasibility of PT-OCT to image the distribution of molecular contrast agents in the mouse retina, including in highly scattering lesions. In the future we will use this method to identify new biomarkers linked with retinal disease.

Longitudinal Trajectories of Ketamine Use among Young Injection Drug Users

PubMed Central

Lankenau, Stephen E.; Bloom, Jennifer Jackson; Shin, Charles

2010-01-01

Background Ketamine is a dissociative anesthetic that became increasing popular in the club and rave scene in the 1980s and 1990s. Reports surfaced in the late 1990s indicating that ketamine was being injected in several U.S. cities by young injection drug users (IDUs). Since all studies on ketamine injection were cross-sectional, a longitudinal study was undertaken in 2005 to determine: characteristics of young IDUs who continue to inject ketamine; frequency of ketamine injection over an extended time period; risks associated with ongoing ketamine injection; and environmental factors that impact patterns of ketamine use. Methods Young IDUs aged 16 to 29 with a history of injecting ketamine (n=101) were recruited from public locations in Los Angeles and followed during a two-year longitudinal study. A semi-structured instrument captured quantitative and qualitative data on patterns of ketamine injection and other drug use. A statistical model sorted IDUs who completed three or more interviews (n=66) into three groups based upon patterns of ketamine injection at baseline and follow-up. Qualitative analysis focused on detailed case studies within each group. Results IDUs recruited at baseline were typically in their early 20s, male, heterosexual, white, and homeless. Longitudinal injection trajectories included: “Moderates,” who injected ketamine several times per year (n=5); “Occasionals,” who injected ketamine approximately once per year (n=21); and “Abstainers,” who did not inject any ketamine during follow-up (n=40). Findings suggest that ketamine is infrequently injected compared to other drugs such as heroin, cocaine, and methamphetamine. Most IDUs who begin injecting ketamine will stop or curb use due to: negative or ambivalent experiences associated with ketamine; an inability to find the drug due to declining supply; or maturing out of injecting drugs more generally. Conclusion Reducing ketamine injection among young IDUs may best be accomplished by targeting particular groups of IDUs identified in this study, such as homeless youth and homeless travelers. PMID:20138747

Comparison of two ultrasound-guided injection techniques targeting the sacroiliac joint region in equine cadavers.

PubMed

Stack, John David; Bergamino, Chiara; Sanders, Ruth; Fogarty, Ursula; Puggioni, Antonella; Kearney, Clodagh; David, Florent

2016-09-20

To compare the accuracy and distribution of injectate for cranial (CR) and caudomedial (CM) ultrasound-guided injections of equine sacroiliac joints. Both sacroiliac joints from 10 lumbosacropelvic specimens were injected using cranial parasagittal (CR; curved 18 gauge, 25 cm spinal needles) and caudomedial (CM; straight 18 gauge, 15 cm spinal needles) ultrasound-guided approaches. Injectate consisted of 4 ml iodinated contrast and 2 ml methylene blue. Computed tomographical (CT) scans were performed before and after injections. Time for needle guidance and repositioning attempts were recorded. The CT sequences were analysed for accuracy and distribution of contrast. Intra-articular contrast was detected in sacroiliac joints following 15/40 injections. The CR and CM approaches deposited injectate ≤2 cm from sacroiliac joint margins following 17/20 and 20/20 injections, respectively. Median distance of closest contrast to the sacroiliac joint was 0.4 cm (interquartile range [IQR]: 1.5 cm) for CR approaches and 0.6 cm (IQR: 0.95 cm) for CM approaches. Cranial injections resulted in injectate contacting lumbosacral intertransverse joints 15/20 times. Caudomedial injections were perivascular 16/20 times. Safety and efficacy could not be established. Cranial and CM ultrasound-guided injections targeting sacroiliac joints were very accurate for periarticular injection, but accuracy was poor for intra-articular injection. Injectate was frequently found in contact with interosseous sacroiliac ligaments, as well as neurovascular and synovial structures in close vicinity of sacroiliac joints.

Modeling and Evaluation of Geophysical Methods for Monitoring and Tracking CO2 Migration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daniels, Jeff

2012-11-30

Geological sequestration has been proposed as a viable option for mitigating the vast amount of CO{sub 2} being released into the atmosphere daily. Test sites for CO{sub 2} injection have been appearing across the world to ascertain the feasibility of capturing and sequestering carbon dioxide. A major concern with full scale implementation is monitoring and verifying the permanence of injected CO{sub 2}. Geophysical methods, an exploration industry standard, are non-invasive imaging techniques that can be implemented to address that concern. Geophysical methods, seismic and electromagnetic, play a crucial role in monitoring the subsurface pre- and post-injection. Seismic techniques have beenmore » the most popular but electromagnetic methods are gaining interest. The primary goal of this project was to develop a new geophysical tool, a software program called GphyzCO2, to investigate the implementation of geophysical monitoring for detecting injected CO{sub 2} at test sites. The GphyzCO2 software consists of interconnected programs that encompass well logging, seismic, and electromagnetic methods. The software enables users to design and execute 3D surface-to-surface (conventional surface seismic) and borehole-to-borehole (cross-hole seismic and electromagnetic methods) numerical modeling surveys. The generalized flow of the program begins with building a complex 3D subsurface geological model, assigning properties to the models that mimic a potential CO{sub 2} injection site, numerically forward model a geophysical survey, and analyze the results. A test site located in Warren County, Ohio was selected as the test site for the full implementation of GphyzCO2. Specific interest was placed on a potential reservoir target, the Mount Simon Sandstone, and cap rock, the Eau Claire Formation. Analysis of the test site included well log data, physical property measurements (porosity), core sample resistivity measurements, calculating electrical permittivity values, seismic data collection, and seismic interpretation. The data was input into GphyzCO2 to demonstrate a full implementation of the software capabilities. Part of the implementation investigated the limits of using geophysical methods to monitor CO{sub 2} injection sites. The results show that cross-hole EM numerical surveys are limited to under 100 meter borehole separation. Those results were utilized in executing numerical EM surveys that contain hypothetical CO{sub 2} injections. The outcome of the forward modeling shows that EM methods can detect the presence of CO{sub 2}.« less

Restoration of the Potosi Dynamic Model 2010

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adushita, Yasmin; Leetaru, Hannes

2014-09-30

In topical Report DOE/FE0002068-1 [2] technical performance evaluations on the Cambrian Potosi Formation were performed through reservoir modeling. The data included formation tops from mud logs, well logs from the VW1 and the CCS1 wells, structural and stratigraphic formation from three dimensional (3D) seismic data, and field data from several waste water injection wells for Potosi Formation. Intention was for two million tons per annum (MTPA) of CO2 to be injected for 20 years. In this Task the 2010 Potosi heterogeneous model (referred to as the "Potosi Dynamic Model 2010" in this report) was re-run using a new injection scenario;more » 3.2 MTPA for 30 years. The extent of the Potosi Dynamic Model 2010, however, appeared too small for the new injection target. It was not sufficiently large enough to accommodate the evolution of the plume. Also, it might have overestimated the injection capacity by enhancing too much the pressure relief due to the relatively close proximity between the injector and the infinite acting boundaries. The new model, Potosi Dynamic Model 2013a, was built by extending the Potosi Dynamic Model 2010 grid to 30 miles x 30 miles (48 km by 48 km), while preserving all property modeling workflows and layering. This model was retained as the base case. Potosi Dynamic Model 2013.a gives an average CO2 injection rate of 1.4 MTPA and cumulative injection of 43 Mt in 30 years, which corresponds to 45% of the injection target. This implies that according to this preliminary model, a minimum of three (3) wells could be required to achieve the injection target. The injectivity evaluation of the Potosi formation will be revisited in topical Report 15 during which more data will be integrated in the modeling exercise. A vertical flow performance evaluation could be considered for the succeeding task to determine the appropriate tubing size, the required injection tubing head pressure (THP) and to investigate whether the corresponding well injection rate falls within the tubing erosional velocity limit. After 30 years, the plume extends 15 miles (24 km) in E-W and 14 miles (22 km) in N-S directions. After injection is completed, the plume continues to migrate laterally, mainly driven by the remaining pressure gradient. After 100 years post-injection, the plume extends 17 miles (27 km) in E-W and 15 miles (24 km) in N-S directions. The increase of reservoir pressure at the end of injection is approximately 370 psia around the injector and gradually decreases away from the well. The reservoir pressure increase is less than 30 psia beyond 14 miles (22 km) away from injector. The initial reservoir pressure is restored after approximately 20 years post-injection. This result, however, is associated with uncertainties on the boundary conditions, and a sensitivity analysis could be considered for the succeeding tasks. It is important to remember that the respective plume extent and areal pressure increase corresponds to an injection of 43 Mt CO2. Should the targeted cumulative injection of 96 Mt be achieved; a much larger plume extent and areal pressure increase could be expected. Re-evaluating the permeability modeling, vugs and heterogeneity distributions, and relative permeability input could be considered for the succeeding Potosi formation evaluations. A simulation using several injectors could also be considered to determine the required number of wells to achieve the injection target while taking into account the pressure interference.« less

Targeted gene deletion of miRNAs in mice by TALEN system.

PubMed

Takada, Shuji; Sato, Tempei; Ito, Yoshiaki; Yamashita, Satoshi; Kato, Tomoko; Kawasumi, Miyuri; Kanai-Azuma, Masami; Igarashi, Arisa; Kato, Tomomi; Tamano, Moe; Asahara, Hiroshi

2013-01-01

Mice are among the most valuable model animal species with an enormous amount of heritage in genetic modification studies. However, targeting genes in mice is sometimes difficult, especially for small genes, such as microRNAs (miRNAs) and targeting genes in repeat sequences. Here we optimized the application of TALEN system for mice and successfully obtained gene targeting technique in mice for intergenic region and series of microRNAs. Microinjection of synthesized RNA of TALEN targeting each gene in one cell stage of embryo was carried out and injected oocytes were transferred into pseudopregnant ICR female mice, producing a high success rate of the targeted deletion of miRNA genes. In our condition, TALEN RNA without poly(A) tail worked better than that of with poly(A) tail. This mutated allele in miRNA was transmitted to the next generation, suggesting the successful germ line transmission of this targeting method. Consistent with our notion of miRNAs maturation mechanism, in homozygous mutant mice of miR-10a, the non- mutated strand of miRNAs expression was completely diminished. This method will lead us to expand and accelerate our genetic research using mice in a high throughput way.

Evaluation of a PSMA-targeted BNF nanoparticle construct

NASA Astrophysics Data System (ADS)

Behnam Azad, Babak; Banerjee, Sangeeta R.; Pullambhatla, Mrudula; Lacerda, Silvia; Foss, Catherine A.; Wang, Yuchuan; Ivkov, Robert; Pomper, Martin G.

2015-02-01

Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo.Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06069e

High resolution ultrasound-guided microinjection for interventional studies of early embryonic and placental development in vivo in mice

PubMed Central

Slevin, John C; Byers, Lois; Gertsenstein, Marina; Qu, Dawei; Mu, Junwu; Sunn, Nana; Kingdom, John CP; Rossant, Janet; Adamson, S Lee

2006-01-01

Background In utero microinjection has proven valuable for exploring the developmental consequences of altering gene expression, and for studying cell lineage or migration during the latter half of embryonic mouse development (from embryonic day 9.5 of gestation (E9.5)). In the current study, we use ultrasound guidance to accurately target microinjections in the conceptus at E6.5–E7.5, which is prior to cardiovascular or placental dependence. This method may be useful for determining the developmental effects of targeted genetic or cellular interventions at critical stages of placentation, gastrulation, axis formation, and neural tube closure. Results In 40 MHz ultrasound images at E6.5, the ectoplacental cone region and proamniotic cavity could be visualized. The ectoplacental cone region was successfully targeted with 13.8 nL of a fluorescent bead suspension with few or no beads off-target in 51% of concepti microinjected at E6.5 (28/55 injected). Seventy eight percent of the embryos survived 2 to 12 days post injection (93/119), 73% (41/56) survived to term of which 68% (38/56) survived and appeared normal one week after birth. At E7.5, the amniotic and exocoelomic cavities, and ectoplacental cone region were discernable. Our success at targeting with few or no beads off-target was 90% (36/40) for the ectoplacental cone region and 81% (35/43) for the exocoelomic cavity but tended to be less, 68% (34/50), for the smaller amniotic cavity. At E11.5, beads microinjected at E7.5 into the ectoplacental cone region were found in the placental spongiotrophoblast layer, those injected into the exocoelomic cavity were found on the surface or within the placental labyrinth, and those injected into the amniotic cavity were found on the surface or within the embryo. Following microinjection at E7.5, survival one week after birth was 60% (26/43) when the amniotic cavity was the target and 66% (19/29) when the target was the ectoplacental cone region. The survival rate was similar in sham experiments, 54% (33/61), for which procedures were identical but no microinjection was performed, suggesting that surgery and manipulation of the uterus were the main causes of embryonic death. Conclusion Ultrasound-guided microinjection into the ectoplacental cone region at E6.5 or E7.5 and the amniotic cavity at E7.5 was achieved with a 7 day postnatal survival of ≥60%. Target accuracy of these sites and of the exocoelomic cavity at E7.5 was ≥51%. We suggest that this approach may be useful for exploring gene function during early placental and embryonic development. PMID:16504164

Revisiting ocean carbon sequestration by direct injection: a global carbon budget perspective

NASA Astrophysics Data System (ADS)

Reith, Fabian; Keller, David P.; Oschlies, Andreas

2016-11-01

In this study we look beyond the previously studied effects of oceanic CO2 injections on atmospheric and oceanic reservoirs and also account for carbon cycle and climate feedbacks between the atmosphere and the terrestrial biosphere. Considering these additional feedbacks is important since backfluxes from the terrestrial biosphere to the atmosphere in response to reducing atmospheric CO2 can further offset the targeted reduction. To quantify these dynamics we use an Earth system model of intermediate complexity to simulate direct injection of CO2 into the deep ocean as a means of emissions mitigation during a high CO2 emission scenario. In three sets of experiments with different injection depths, we simulate a 100-year injection period of a total of 70 GtC and follow global carbon cycle dynamics over another 900 years. In additional parameter perturbation runs, we varied the default terrestrial photosynthesis CO2 fertilization parameterization by ±50 % in order to test the sensitivity of this uncertain carbon cycle feedback to the targeted atmospheric carbon reduction through direct CO2 injections. Simulated seawater chemistry changes and marine carbon storage effectiveness are similar to previous studies. As expected, by the end of the injection period avoided emissions fall short of the targeted 70 GtC by 16-30 % as a result of carbon cycle feedbacks and backfluxes in both land and ocean reservoirs. The target emissions reduction in the parameter perturbation simulations is about 0.2 and 2 % more at the end of the injection period and about 9 % less to 1 % more at the end of the simulations when compared to the unperturbed injection runs. An unexpected feature is the effect of the model's internal variability of deep-water formation in the Southern Ocean, which, in some model runs, causes additional oceanic carbon uptake after injection termination relative to a control run without injection and therefore with slightly different atmospheric CO2 and climate. These results of a model that has very low internal climate variability illustrate that the attribution of carbon fluxes and accounting for injected CO2 may be very challenging in the real climate system with its much larger internal variability.

Application of a Real-Time, Calculable Limiting Form of the Renyi Entropy for Molecular Imaging of Tumors

PubMed Central

Marsh, J. N.; Wallace, K. D.; McCarthy, J. E.; Wickerhauser, M. V.; Maurizi, B. N.; Lanza, G. M.; Wickline, S. A.; Hughes, M. S.

2011-01-01

Previously, we reported new methods for ultrasound signal characterization using entropy, Hf; a generalized entropy, the Renyi entropy, If(r); and a limiting form of Renyi entropy suitable for real-time calculation, If,∞. All of these quantities demonstrated significantly more sensitivity to subtle changes in scattering architecture than energy-based methods in certain settings. In this study, the real-time calculable limit of the Renyi entropy, If,∞, is applied for the imaging of angiogenic murine neovasculature in a breast cancer xenograft using a targeted contrast agent. It is shown that this approach may be used to detect reliably the accumulation of targeted nanoparticles at five minutes post-injection in this in vivo model. PMID:20679020

Site-targeted non-viral gene delivery by direct DNA injection into the pancreatic parenchyma and subsequent in vivo electroporation in mice.

PubMed

Sato, Masahiro; Inada, Emi; Saitoh, Issei; Ohtsuka, Masato; Nakamura, Shingo; Sakurai, Takayuki; Watanabe, Satoshi

2013-11-01

The pancreas is considered an important gene therapy target because the organ is the site of several high burden diseases, including diabetes mellitus, cystic fibrosis, and pancreatic cancer. We aimed to develop an efficient in vivo gene delivery system using non-viral DNA. Direct intra-parenchymal injection of a solution containing circular plasmid pmaxGFP DNA was performed on adult anesthetized ICR female mice. The injection site was sandwiched with a pair of tweezer-type electrode disks, and electroporated using a square-pulse generator. Green fluorescent protein (GFP) expression within the injected pancreatic portion was observed one day after gene delivery. GFP expression reduced to baseline within a week of transfection. Application of voltages over 40 V resulted in tissue damage during electroporation. We demonstrate that electroporation is effective for safe and efficient transfection of pancreatic cells. This novel gene delivery method to the pancreatic parenchyma may find application in gene therapy strategies for pancreatic diseases and in investigation of specific gene function in situ. © 2013 The Authors. Biotechnology Journal published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptions are made.

Localized time-lapse elastic waveform inversion using wavefield injection and extrapolation: 2-D parametric studies

NASA Astrophysics Data System (ADS)

Yuan, Shihao; Fuji, Nobuaki; Singh, Satish; Borisov, Dmitry

2017-06-01

We present a methodology to invert seismic data for a localized area by combining source-side wavefield injection and receiver-side extrapolation method. Despite the high resolving power of seismic full waveform inversion, the computational cost for practical scale elastic or viscoelastic waveform inversion remains a heavy burden. This can be much more severe for time-lapse surveys, which require real-time seismic imaging on a daily or weekly basis. Besides, changes of the structure during time-lapse surveys are likely to occur in a small area rather than the whole region of seismic experiments, such as oil and gas reservoir or CO2 injection wells. We thus propose an approach that allows to image effectively and quantitatively the localized structure changes far deep from both source and receiver arrays. In our method, we perform both forward and back propagation only inside the target region. First, we look for the equivalent source expression enclosing the region of interest by using the wavefield injection method. Second, we extrapolate wavefield from physical receivers located near the Earth's surface or on the ocean bottom to an array of virtual receivers in the subsurface by using correlation-type representation theorem. In this study, we present various 2-D elastic numerical examples of the proposed method and quantitatively evaluate errors in obtained models, in comparison to those of conventional full-model inversions. The results show that the proposed localized waveform inversion is not only efficient and robust but also accurate even under the existence of errors in both initial models and observed data.

Extemporaneously preparative biodegradable injectable polymer systems exhibiting temperature-responsive irreversible gelation.

PubMed

Yoshida, Yasuyuki; Takata, Kazuyuki; Takai, Hiroki; Kawahara, Keisuke; Kuzuya, Akinori; Ohya, Yuichi

2017-10-01

On clinical application of biodegradable injectable polymer (IP) systems, quick extemporaneous preparation of IP formulations and longer duration time gel state after injection into the body are the important targets to be developed. Previously, we had reported temperature-responsive covalent gelation systems via bio-orthogonal thiol-ene reaction by 'mixing strategy' of amphiphilic biodegradable tri-block copolymer (tri-PCG) attaching acryloyl groups on both termini (tri-PCG-Acryl) with reactive polythiol. In other previous works, we found 'freeze-dry with PEG/dispersion' method as quick extemporaneous preparation method of biodegradable IP formulations. In this study, we applied this quick preparative method to the temperature-triggered covalent gelation system. The instant formulation (D-sample) could be prepared by 'freeze-dry with PEG/dispersion' just mixing of tri-PCG-Acryl micelle dispersion and tri-PCG/DPMP micelle dispersion with PEG, that can be prepared in 30 s from the dried samples. The obtained D-sample showed irreversible gelation and long duration time of gel state, which was basically the same as the formulations prepared by the usual heating dissolution method (S-sample). Interestingly, the D-sample could maintain its sol state for a longer time (24 h) after preparing the formulation at r.t. compared with the S-sample, which became a gel in 3 h after preparing. The IP system showed good biocompatibility and long duration time of the gel state after subcutaneous implantation. These characteristics of D-samples, quick extemporaneous preparation and high stability in the sol state before injection, would be very convenient in a clinical setting.

Effects of Ionization in a Laser Wakefield Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuffey, C.; Schumaker, W.; Matsuoka, T.

2010-11-04

Experimental results are presented from studies of the ionization injection process in laser wakefield acceleration using the Hercules laser with laser power up to 100 TW. Gas jet targets consisting of gas mixtures reduced the density threshold required for electron injection and increased the maximum beam charge. Gas mixture targets produced smooth beams even at densities which would produce severe beam breakup in pure He targets and the divergence was found to increase with gas mixture pressure.

[Observational study of outpatient unit duration of stay depending on the route of administration (intravenous vs subcutaneous) for a targeted therapy].

PubMed

Despiau, Frédéric; Zagala, Yann; Delord, Jean-Pierre; Montastruc, Marion; Lacaze, Jean-Louis; Ferrand, Régis; Bombail, Marie

2017-10-01

New routes of administration available for some targeted therapies, especially subcutaneous injections, have an impact not only on the patients' daycare experience, but also on the unit's organization. This observational study conducted on 48 voluntary patients at the Institut universitaire du cancer Toulouse-Oncopole shows that the mean duration of the outpatient unit stay is diminished by one hour when a subcutaneous injection is used instead of an intravenous route. This duration decrease is mainly caused by an 82% average reduction in treatment duration. However, the waiting times before and after the treatment itself are not significantly impacted. Organizational methods related to the treatment prescription and preparation remain indeed the same. Anticipated prescription is not noticeably impacted either. This reduction of the duration of stay will truly be obtained if the whole unit's organization is adapted. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

CT-guided robotically-assisted infiltration of foot and ankle joints.

PubMed

Wiewiorski, Martin; Valderrabano, Victor; Kretzschmar, Martin; Rasch, Helmut; Markus, Tanja; Dziergwa, Severine; Kos, Sebastian; Bilecen, Deniz; Jacob, Augustinus Ludwig

2009-01-01

It was our aim to describe a CT-guided robotically-assisted infiltration technique for diagnostic injections in foot and ankle orthopaedics. CT-guided mechatronically-assisted joint infiltration was performed on 16 patients referred to the orthopaedic department for diagnostic foot and ankle assessment. All interventions were performed using an INNOMOTION-assistance device on a multislice CT scanner in an image-guided therapy suite. Successful infiltration was defined as CT localization of contrast media in the target joint. Additionally, pre- and post-interventional VAS pain scores were assessed. All injections (16/16 joints) were technically successful. Contrast media deposit was documented in all targeted joints. Significant relief of pain was noted by all 16 patients (p<0.01). CT-guided robotically-assisted intervention is an exact, reliable and safe application method for diagnostic infiltration of midfoot and hindfoot joints. The high accuracy and feasibility in a clinical environment make it a viable alternative to the commonly used fluoroscopic-guided procedures.

Physiologically-Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long Acting Nanoformulations for HIV

PubMed Central

Rajoli, Rajith KR; Back, David J; Rannard, Steve; Meyers, Caren Freel; Flexner, Charles; Owen, Andrew; Siccardi, Marco

2014-01-01

Background and Objectives Antiretrovirals (ARVs) are currently used for the treatment and prevention of HIV infection. Poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying ARV administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight ARVs through physiologically-based pharmacokinetic (PBPK) modelling. Methods A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations Results The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control release rate can be addressed. Conclusions These data may help inform the target product profiles for LA ARV reformulation strategies. PMID:25523214

Targeted Injection of a Biocomposite Material Alters Macrophage and Fibroblast Phenotype and Function following Myocardial Infarction: Relation to Left Ventricular Remodeling

PubMed Central

McGarvey, Jeremy R.; Pettaway, Sara; Shuman, James A.; Novack, Craig P.; Zellars, Kia N.; Freels, Parker D.; Echols, Randall L.; Burdick, Jason A.; Gorman, Joseph H.; Gorman, Robert C.

2014-01-01

A treatment target for progressive left ventricular (LV) remodeling prevention following myocardial infarction (MI) is to affect structural changes directly within the MI region. One approach is through targeted injection of biocomposite materials, such as calcium hydroxyapatite microspheres (CHAM), into the MI region. In this study, the effects of CHAM injections upon key cell types responsible for the MI remodeling process, the macrophage and fibroblast, were examined. MI was induced in adult pigs before randomization to CHAM injections (20 targeted 0.1-ml injections within MI region) or saline. At 7 or 21 days post-MI (n = 6/time point per group), cardiac magnetic resonance imaging was performed, followed by macrophage and fibroblast isolation. Isolated macrophage profiles for monocyte chemotactic macrophage inflammatory protein-1 as measured by real-time polymerase chain reaction increased at 7 days post-MI in the CHAM group compared with MI only (16.3 ± 6.6 versus 1.7 ± 0.6 cycle times values, P < 0.05), and were similar by 21 days post-MI. Temporal changes in fibroblast function and smooth muscle actin (SMA) expression relative to referent control (n = 5) occurred with MI. CHAM induced increases in fibroblast proliferation, migration, and SMA expression—indicative of fibroblast transformation. By 21 days, CHAM reduced LV dilation (diastolic volume: 75 ± 2 versus 97 ± 4 ml) and increased function (ejection fraction: 48 ± 2% versus 38 ± 2%) compared with MI only (both P < 0.05). This study identified that effects on macrophage and fibroblast differentiation occurred with injection of biocomposite material within the MI, which translated into reduced adverse LV remodeling. These unique findings demonstrate that biomaterial injections impart biologic effects upon the MI remodeling process over any biophysical effects. PMID:25022514

Targeted Ultrasound-Guided Perineural Hydrodissection of the Sciatic Nerve for the Treatment of Piriformis Syndrome.

PubMed

Burke, Christopher J; Walter, William R; Adler, Ronald S

2018-05-01

Piriformis syndrome is a common cause of lumbar, gluteal, and thigh pain, frequently associated with sciatic nerve symptoms. Potential etiologies include muscle injury or chronic muscle stretching associated with gait disturbances. There is a common pathological end pathway involving hypertrophy, spasm, contracture, inflammation, and scarring of the piriformis muscle, leading to impingement of the sciatic nerve. Ultrasound-guided piriformis injections are frequently used in the treatment of these pain syndromes, with most of the published literature describing injection of the muscle. We describe a safe, effective ultrasound-guided injection technique for the treatment of piriformis syndrome using targeted sciatic perineural hydrodissection followed by therapeutic corticosteroid injection.

Detection of seventy-two anabolic and androgenic steroids and/or their esters in horse hair using ultra-high performance liquid chromatography-high resolution mass spectrometry in multiplexed targeted MS2 mode and gas chromatography-tandem mass spectrometry.

PubMed

Choi, Timmy L S; Kwok, Karen Y; Kwok, Wai Him; Tsoi, Yeuki Y K; Wong, Jenny K Y; Wan, Terence S M

2018-06-20

Anabolic and androgenic steroids (AAS) are banned substances in both human and equine sports. They are often administered intramuscularly to horses in esterified forms for the purpose of extending their time of action. The authors' laboratory has previously reported an UHPLC/HRMS method using quadrupole-Orbitrap mass spectrometer in full scan and parallel reaction monitoring (PRM) mode for the detection of 48 AAS and/or their esters in horse hair. However, two injections were required due to the long duty cycle time. In this paper, an UHPLC/HRMS method using multiplexed targeted MS 2 mode was developed and validated to improve the coverage to 65 AAS and/or their esters in a single injection. In addition, a GC/MS/MS method in selected reaction monitoring (SRM) mode was developed to screen for another seven AAS and/or their esters not adequately covered by the UHPLC/HRMS method using the same sample extract after derivatisation with pentafluoropropionic anhydride. The UHPLC/HRMS and GC/MS/MS methods in combination allowed the detection of 72 AAS and/or their esters with estimated limits of detection down to sub to low ppb levels with good interday precision. Method applicability was demonstrated by the detection of boldione and 4-androstenedione in two out-of-competition hair samples and testosterone propionate in a referee hair sample. Copyright © 2018 Elsevier B.V. All rights reserved.

Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature

PubMed Central

Gerlag, Danielle M; Borges, Eric; Tak, Paul P; Ellerby, H Michael; Bredesen, Dale E; Pasqualini, Renata; Ruoslahti, Erkki; Firestein, Gary S

2001-01-01

Because angiogenesis plays a major role in the perpetuation of inflammatory arthritis, we explored a method for selectively targeting and destroying new synovial blood vessels. Mice with collagen-induced arthritis were injected intravenously with phage expressing an RGD motif. In addition, the RGD peptide (RGD-4C) was covalently linked to a proapoptotic heptapeptide dimer, D(KLAKLAK)2, and was systemically administered to mice with collagen-induced arthritis. A phage displaying an RGD-containing cyclic peptide (RGD-4C) that binds selectively to the αvβ3 and αvβ5 integrins accumulated in inflamed synovium but not in normal synovium. Homing of RGD-4C phage to inflamed synovium was inhibited by co-administration of soluble RGD-4C. Intravenous injections of the RGD-4C–D(KLAKLAK)2 chimeric peptide significantly decreased clinical arthritis and increased apoptosis of synovial blood vessels, whereas treatment with vehicle or uncoupled mixture of the RGD-4C and the untargeted proapoptotic peptide had no effect. Targeted apoptosis of synovial neovasculature can induce apoptosis and suppress clinical arthritis. This form of therapy has potential utility in the treatment of inflammatory arthritis. PMID:11714389

CRISPR/Cas-mediated knock-in via non-homologous end-joining in the crustacean Daphnia magna.

PubMed

Kumagai, Hitoshi; Nakanishi, Takashi; Matsuura, Tomoaki; Kato, Yasuhiko; Watanabe, Hajime

2017-01-01

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) is widely used for mediating the knock-in of foreign DNA into the genomes of various organisms. Here, we report a process of CRISPR/Cas-mediated knock-in via non-homologous end joining by the direct injection of Cas9/gRNA ribonucleoproteins (RNPs) in the crustacean Daphnia magna, which is a model organism for studies on toxicology, ecology, and evolution. First, we confirmed the cleavage activity of Cas9 RNPs comprising purified Cas9 proteins and gRNAs in D. magna. We used a gRNA that targets exon 10 of the eyeless gene. Cas9 proteins were incubated with the gRNAs and the resulting Cas9 RNPs were injected into D. magna eggs, which led to a typical phenotype of the eyeless mutant, i.e., eye deformity. The somatic and heritable mutagenesis efficiencies were up to 96% and 40%, respectively. Second, we tested the CRISPR/Cas-mediated knock-in of a plasmid by the injection of Cas9 RNPs. The donor DNA plasmid harboring the fluorescent reporter gene was designed to contain the gRNA recognition site. The co-injection of Cas9 RNPs together with the donor DNAs resulted in generation of one founder animal that produced fluorescent progenies. This transgenic Daphnia had donor DNA at the targeted genomic site, which suggested the concurrent cleavage of the injected plasmid DNA and genomic DNA. Owing to its simplicity and ease of experimental design, we suggest that the CRISPR/Cas-mediated knock-in method represents a promising tool for studying functional genomics in D. magna.

CRISPR/Cas-mediated knock-in via non-homologous end-joining in the crustacean Daphnia magna

PubMed Central

Kumagai, Hitoshi; Nakanishi, Takashi; Matsuura, Tomoaki; Kato, Yasuhiko

2017-01-01

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) is widely used for mediating the knock-in of foreign DNA into the genomes of various organisms. Here, we report a process of CRISPR/Cas-mediated knock-in via non-homologous end joining by the direct injection of Cas9/gRNA ribonucleoproteins (RNPs) in the crustacean Daphnia magna, which is a model organism for studies on toxicology, ecology, and evolution. First, we confirmed the cleavage activity of Cas9 RNPs comprising purified Cas9 proteins and gRNAs in D. magna. We used a gRNA that targets exon 10 of the eyeless gene. Cas9 proteins were incubated with the gRNAs and the resulting Cas9 RNPs were injected into D. magna eggs, which led to a typical phenotype of the eyeless mutant, i.e., eye deformity. The somatic and heritable mutagenesis efficiencies were up to 96% and 40%, respectively. Second, we tested the CRISPR/Cas-mediated knock-in of a plasmid by the injection of Cas9 RNPs. The donor DNA plasmid harboring the fluorescent reporter gene was designed to contain the gRNA recognition site. The co-injection of Cas9 RNPs together with the donor DNAs resulted in generation of one founder animal that produced fluorescent progenies. This transgenic Daphnia had donor DNA at the targeted genomic site, which suggested the concurrent cleavage of the injected plasmid DNA and genomic DNA. Owing to its simplicity and ease of experimental design, we suggest that the CRISPR/Cas-mediated knock-in method represents a promising tool for studying functional genomics in D. magna. PMID:29045453

Injectable silk foams for the treatment of cervical insufficiency

NASA Astrophysics Data System (ADS)

Fournier, Eric P.

Preterm birth is the leading cause of neonatal mortality, resulting in over 4,000 deaths each year. A significant risk factor for preterm birth is cervical insufficiency, the weakening and subsequent deformation of cervical tissue. Cervical insufficiency is both detectable and treatable but current treatments are lacking. The most common approach requires multiple invasive procedures. This work investigates the injection of silk foams, a minimally-invasive method for supporting cervical tissue. Silk offers many advantages for use as a biomaterial including strength, versatility, and biocompatibility. Injectable silk foams will minimize patient discomfort while also providing more targeted and personalized treatment. A battery of mechanical testing was undertaken to determine silk foam response under physiologically relevant loading and environmental conditions. Mechanical testing was paired with analysis of foam morphology and structure that illustrated the effects of injection on pore geometry and size. Biological response to silk foams was evaluated using an in vitro degradation study and subcutaneous in vivo implantation in a mouse model. Results showed that foams exceeded the mechanical requirements for stiffening cervical tissue, although the current injection process limits foam size. Injection was shown to cause measurable but localized foam deformation. This work indicates that silk foams are a feasible treatment option for cervical insufficiency but challenges remain with foam delivery.

Simultaneous analysis of multiple classes of antimicrobials in environmental water samples using SPE coupled with UHPLC-ESI-MS/MS and isotope dilution.

PubMed

Tran, Ngoc Han; Chen, Hongjie; Do, Thanh Van; Reinhard, Martin; Ngo, Huu Hao; He, Yiliang; Gin, Karina Yew-Hoong

2016-10-01

A robust and sensitive analytical method was developed for the simultaneous analysis of 21 target antimicrobials in different environmental water samples. Both single SPE and tandem SPE cartridge systems were investigated to simultaneously extract multiple classes of antimicrobials. Experimental results showed that good extraction efficiencies (84.5-105.6%) were observed for the vast majority of the target analytes when extraction was performed using the tandem SPE cartridge (SB+HR-X) system under an extraction pH of 3.0. HPLC-MS/MS parameters were optimized for simultaneous analysis of all the target analytes in a single injection. Quantification of target antimicrobials in water samples was accomplished using 15 isotopically labeled internal standards (ILISs), which allowed the efficient compensation of the losses of target analytes during sample preparation and correction of matrix effects during UHPLC-MS/MS as well as instrument fluctuations in MS/MS signal intensity. Method quantification limit (MQL) for most target analytes based on SPE was below 5ng/L for surface waters, 10ng/L for treated wastewater effluents, and 15ng/L for raw wastewater. The method was successfully applied to detect and quantify the occurrence of the target analytes in raw influent, treated effluent and surface water samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhanced tolerance and antitumor efficacy by docetaxel-loaded albumin nanoparticles.

PubMed

Tang, Xiaolei; Wang, Guijun; Shi, Runjie; Jiang, Ke; Meng, Lingtong; Ren, Hao; Wu, Jinhui; Hu, Yiqiao

2016-10-01

Docetaxel is one of the most active chemotherapeutic agents for cancer treatment. The traditional docetaxel injection (TAXOTERE®) is currently formulated in the surfactant polysorbate 80, which has been associated with severe adverse reactions. To avoid the use of polysorbate 80 as well as to reduce the systemic toxicity of docetaxel, in this study, docetaxel-loaded albumin nanoparticles were fabricated by a novel simple self-assembly method. The resulting nanoparticles showed a mean diameter size of 150 nm. After being encapsulated into nanoparticles, docetaxel displayed similar cytotoxicity to traditional injection. Since polysorbate 80 was not involved in nanoparticles, the hemolysis was completely eliminated. The maximal tolerance dose of nanoparticles was also increased, which allowed a higher dose to be safely intravenously injected and produced ideal antitumor effects. The 150 nm diameter also allowed the nanoparticles to accumulate in tumor tissue via the enhanced permeability and retention effect. The passive targeting ability further caused the higher antitumor effects of nanoparticles than that of traditional injection at the same dose (7.5 mg/kg). Therefore, docetaxel-loaded albumin nanoparticles fabricated by our strategy showed higher promise in their safety and effectiveness than the traditional docetaxel injection.

Optimization of programmed-temperature vaporization injection preparative capillary GC for compound specific radiocarbon analysis.

PubMed

Zhang, Xinyu; Zhao, Liang; Wang, Yexin; Xu, Yunping; Zhou, Liping

2013-07-01

Preparative capillary GC (PCGC) is a powerful tool for the separation and purification of compounds from any complex matrix, which can be used for compound-specific radiocarbon analysis. However, the effect of PCGC parameters on the trapping efficiency is not well understood. Here, we present a comprehensive study on the optimization of parameters based on 11 reference compounds with different physicochemical properties. Under the optimum conditions, the trapping efficiencies of these 11 compounds (including high-boiling-point n-hentriacontane and methyl lignocerate) are about 80% (60-89%). The isolation of target compounds from standard solutions, plant and soil samples demonstrates that our optimized method is applicable for different classes of compounds including n-alkanes, fatty acid esters, long-chain fatty alcohol esters, polycyclic aromatic hydrocarbons (PAHs) and steranes. By injecting 25 μL in large volume injection mode, over 100 μg, high purity (>90%) target compounds are harvested within 24 h. The recovery ranges of two real samples are about 70% (59.9-83.8%) and about 83% (77.2-88.5%), respectively. Compared to previous studies, our study makes significant improvement in the recovery of PCGC, which is important for its wide application in biogeochemistry, environmental sciences, and archaeology. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Apparatus and method for nanoflow liquid jet and serial femtosecond x-ray protein crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogan, Michael J.; Laksmono, Hartawan; Sierra, Raymond G.

Techniques for nanoflow serial femtosecond x-ray protein crystallography include providing a sample fluid by mixing a plurality of a first target of interest with a carrier fluid and injecting the sample fluid into a vacuum chamber at a rate less than about 4 microliters per minute. In some embodiments, the carrier fluid has a viscosity greater than about 3 centipoise.

Evaluation of the Possible Utilization of 68Ga-DOTATOC in Diagnosis of Adenocarcinoma Breast Cancer

PubMed Central

Zolghadri, Samaneh; Naderi, Mojdeh; Yousefnia, Hassan; Alirezapour, Behrouz; Beiki, Davood

2018-01-01

Objective(s): Studies have indicated advantageous properties of [DOTA-DPhe1, Tyr3] octreotide (DOTATOC) in tumor models and labeling with gallium. Breast cancer is the second leading cause of cancer mortality in women, and most of these cancers are often an adenocarcinoma. Due to the importance of target to non-target ratios in the efficacy of diagnosis, the pharmacokinetic of 68Ga-DOTATOC in an adenocarcinoma breast cancer animal model was studied in this research, and the optimized time for imaging was determined. Methods: 68Ga was obtained from 68Ge/68Ga generator. The complex was prepared at optimized conditions. Radiochemical purity of the complex was checked using both HPLC and ITLC methods. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer. Also, PET/CT imaging was performed up to 120 min post injection. Results: The complex was produced with radiochemical purity of greater than 98% and specific activity of about 40 GBq/mM at optimized conditions. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer indicated fast blood clearance and significant uptake in the tumor. Significant tumor: blood and tumor:muscle uptake ratios were observed even at early times post-injection. PET/CT images were also confirmed the considerable accumulation of the tracer in the tumor. Conclusion: Generally, the results proved the possible application of the radiolabelled complex for the detection of the adenocarcinoma breast cancer and according to the pharmacokenitic data, the suitable time for imaging was determined as at least 30 min after injection. PMID:29333466

[Reducing fear in preschool children receiving intravenous injections].

PubMed

Hsieh, Yi-Chuan; Liu, Hui-Tzu; Cho, Yen-Hua

2012-06-01

Our pediatric medical ward administers an average of 80 intravenous injections to preschool children. We found that 91.1% exhibit behavior indicative of fear and anxiety. Over three-quarters (77.8%) of this number suffer severe fear and actively resist receiving injections. Such behavior places a greater than normal burden on human and material resources and often gives family members negative impressions that lower their trust in the healthcare service while raising nurse-patient tensions. Using observation and interviews, we found primary factors in injection fear to be: Past negative experiences, lack of adequate prior communication, measures taken to preemptively control child resistance, and default cognitive behavioral strategies from nursing staff. This project worked to develop a strategy to reduce cases of severe injection fear in preschool children from 77.8% to 38.9% and achieve a capacity improvement target for members of 50%. Our team identified several potential strategy solutions from research papers and books between August 1st, 2009 and April 30th, 2010. Our proposed method included therapeutic games, self-selection of injection position, and cognitive behavioral strategies to divert attention. Other measures were also specified as standard operating procedures for administering pediatric intravenous injections. We applied the strategy on 45 preschool children and identified a post-injection "severe fear" level of 37.8%. This project was designed to reduce fear in children to make them more accepting of vaccinations and to enhance children's positive treatment experience in order to raise nursing care quality.

Autologous Platelet-Poor Plasma Gel for Injection Laryngoplasty

PubMed Central

Woo, Seung Hoon; Kim, Jin Pyeong; Park, Jung Je; Chung, Phil-Sang

2013-01-01

Purpose To overcome the potential disadvantages of the use of foreign materials and autologous fat or collagen, we introduce here an autologous plasma gel for injection laryngoplasty. The purpose of this study was to present a new injection material, a plasma gel, and to discuss its clinical effectiveness. Materials and Methods From 2 mL of blood, the platelet poor serum layer was collected and heated at 100℃ for 12 min to form a plasma gel. The plasma gel was then injected into a targeted site; the safety and efficacy thereof were evaluated in 30 rats. We also conducted a phase I/II clinical study of plasma gel injection laryngoplasty in 11 unilateral vocal fold paralysis patients. Results The plasma gel was semi-solid and an easily injectable material. Of note, plasma gel maintains the same consistency for up to 1 year in a sealed bottle. However, exposure to room air causes the plasma gel to disappear within 1 month. In our animal study, the autologous plasma gel remained in situ for 6 months in animals with minimal inflammation. Clinical study showed that vocal cord palsy was well compensated for with the plasma gel in all patients at two months after injection with no significant complications. Jitter, shimmer, maximum, maximum phonation time (MPT) and mean voice handicap index (VHI) also improved significantly after plasma gel injection. However, because the injected plasma gel was gradually absorbed, 6 patients needed another injection, while the gel remained in place in 2 patients. Conclusion Injection laryngoplasty with autologous plasma gel may be a useful and safe treatment option for temporary vocal cord palsy. PMID:24142660

In vivo brain electrophoresis - a novel method for chemotherapy of CNS diseases.

PubMed

Ammirati, Mario; Lamki, Tariq; Chitnis, Girish; Yang, Xiangyu; Russell, Duncan; Coble, Dondrae; Kaur, Balveen; Knopp, Michael; Moore, Sarah; Ziaie, Babak

2015-05-01

The blood-brain barrier (BBB) is a protective mechanism that does its job superbly. So much so, that hitherto, brain chemotherapy has been limited by it. In fact, very few agents are effective against brain disease due to the inherent difficulties of penetrating the BBB. We describe a novel, extremely focused method for delivering drugs to specific diseased areas. This innovative method directly delivers putative substances to the pathological area, bypassing the BBB. Treatment of brain diseases could be improved by targeted, controlled delivery of therapeutic substances to diseased cerebral areas. Our described novel method - in vivo electrophoresis - achieves this. This technique was evaluated in beagles after craniotomy was performed and a custom-designed plate with electrodes inserted. The delivery of charged substances to selected areas with predictably guided movement was achieved via a created electrical field. Gadolinium, a compound unable to cross the BBB, was injected intracerebrally whereas an electrical field was created using the implanted electrodes surrounding the injection area. The electrical field-guided Gadolinium movement was evaluated using MRI. Gadolinium was moved predictably using the created electrical field without complications. The experiment successfully demonstrated controlled movement of the substance. This technique can significantly change treatment of brain diseases because substances: i) may be moved in a controlled, predictable way - exponentially increasing therapeutic interactions with the target; and ii) no longer need to conform to constraints dictated by the BBB (molecular mass < 500 d; lipophilic), thereby increasing potential number of usable substances.

Flux-Level Transit Injection Experiments with NASA Pleiades Supercomputer

NASA Astrophysics Data System (ADS)

Li, Jie; Burke, Christopher J.; Catanzarite, Joseph; Seader, Shawn; Haas, Michael R.; Batalha, Natalie; Henze, Christopher; Christiansen, Jessie; Kepler Project, NASA Advanced Supercomputing Division

2016-06-01

Flux-Level Transit Injection (FLTI) experiments are executed with NASA's Pleiades supercomputer for the Kepler Mission. The latest release (9.3, January 2016) of the Kepler Science Operations Center Pipeline is used in the FLTI experiments. Their purpose is to validate the Analytic Completeness Model (ACM), which can be computed for all Kepler target stars, thereby enabling exoplanet occurrence rate studies. Pleiades, a facility of NASA's Advanced Supercomputing Division, is one of the world's most powerful supercomputers and represents NASA's state-of-the-art technology. We discuss the details of implementing the FLTI experiments on the Pleiades supercomputer. For example, taking into account that ~16 injections are generated by one core of the Pleiades processors in an hour, the “shallow” FLTI experiment, in which ~2000 injections are required per target star, can be done for 16% of all Kepler target stars in about 200 hours. Stripping down the transit search to bare bones, i.e. only searching adjacent high/low periods at high/low pulse durations, makes the computationally intensive FLTI experiments affordable. The design of the FLTI experiments and the analysis of the resulting data are presented in “Validating an Analytic Completeness Model for Kepler Target Stars Based on Flux-level Transit Injection Experiments” by Catanzarite et al. (#2494058).Kepler was selected as the 10th mission of the Discovery Program. Funding for the Kepler Mission has been provided by the NASA Science Mission Directorate.

Drug-target interaction prediction using ensemble learning and dimensionality reduction.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2017-10-01

Experimental prediction of drug-target interactions is expensive, time-consuming and tedious. Fortunately, computational methods help narrow down the search space for interaction candidates to be further examined via wet-lab techniques. Nowadays, the number of attributes/features for drugs and targets, as well as the amount of their interactions, are increasing, making these computational methods inefficient or occasionally prohibitive. This motivates us to derive a reduced feature set for prediction. In addition, since ensemble learning techniques are widely used to improve the classification performance, it is also worthwhile to design an ensemble learning framework to enhance the performance for drug-target interaction prediction. In this paper, we propose a framework for drug-target interaction prediction leveraging both feature dimensionality reduction and ensemble learning. First, we conducted feature subspacing to inject diversity into the classifier ensemble. Second, we applied three different dimensionality reduction methods to the subspaced features. Third, we trained homogeneous base learners with the reduced features and then aggregated their scores to derive the final predictions. For base learners, we selected two classifiers, namely Decision Tree and Kernel Ridge Regression, resulting in two variants of ensemble models, EnsemDT and EnsemKRR, respectively. In our experiments, we utilized AUC (Area under ROC Curve) as an evaluation metric. We compared our proposed methods with various state-of-the-art methods under 5-fold cross validation. Experimental results showed EnsemKRR achieving the highest AUC (94.3%) for predicting drug-target interactions. In addition, dimensionality reduction helped improve the performance of EnsemDT. In conclusion, our proposed methods produced significant improvements for drug-target interaction prediction. Copyright © 2017 Elsevier Inc. All rights reserved.

Massive Fabrication of Polymer Microdiscs by Phase Separation and Freestanding Process.

PubMed

Zhang, Hong; Fujii, Mao; Okamura, Yosuke; Zhang, Li; Takeoka, Shinji

2016-06-29

We present a facile method to fabricate polymer thin films with tens of nanometers thickness and several micrometers size (also called "microdiscs" herein) by applying phase separation of polymer blend. A water-soluble supporting layer is employed to obtain a freestanding microdisc suspension. Owing to their miniaturized size, microdiscs can be injected through a syringe needle. Herein, poly(d,l-lactic acid) microdiscs were fabricated with various thicknesses and sizes, in the range from ca. 10 to 60 nm and from ca. 1.0 to 10.0 μm, respectively. Magnetic nanoparticles were deposited on polymer microdiscs with a surface coating method. The magnetic manipulation of microdiscs in a liquid environment under an external magnetic field was achieved with controllable velocity by adjusting the microdisc dimensions and the loading amount of magnetic components. Such biocompatible polymer microdiscs are expected to serve as injectable vehicles for targeted drug delivery.

Quantitative comparison of tumor delivery for multiple targeted nanoparticles simultaneously by multiplex ICP-MS.

PubMed

Elias, Andrew; Crayton, Samuel H; Warden-Rothman, Robert; Tsourkas, Andrew

2014-07-28

Given the rapidly expanding library of disease biomarkers and targeting agents, the number of unique targeted nanoparticles is growing exponentially. The high variability and expense of animal testing often makes it unfeasible to examine this large number of nanoparticles in vivo. This often leads to the investigation of a single formulation that performed best in vitro. However, nanoparticle performance in vivo depends on many variables, many of which cannot be adequately assessed with cell-based assays. To address this issue, we developed a lanthanide-doped nanoparticle method that allows quantitative comparison of multiple targeted nanoparticles simultaneously. Specifically, superparamagnetic iron oxide (SPIO) nanoparticles with different targeting ligands were created, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood and resected tumor samples.

Chaining direct memory access data transfer operations for compute nodes in a parallel computer

DOEpatents

Archer, Charles J.; Blocksome, Michael A.

2010-09-28

Methods, systems, and products are disclosed for chaining DMA data transfer operations for compute nodes in a parallel computer that include: receiving, by an origin DMA engine on an origin node in an origin injection FIFO buffer for the origin DMA engine, a RGET data descriptor specifying a DMA transfer operation data descriptor on the origin node and a second RGET data descriptor on the origin node, the second RGET data descriptor specifying a target RGET data descriptor on the target node, the target RGET data descriptor specifying an additional DMA transfer operation data descriptor on the origin node; creating, by the origin DMA engine, an RGET packet in dependence upon the RGET data descriptor, the RGET packet containing the DMA transfer operation data descriptor and the second RGET data descriptor; and transferring, by the origin DMA engine to a target DMA engine on the target node, the RGET packet.

Target location after deep cerebral biopsies using low-volume air injection in 75 patients. Results and technical note.

PubMed

Poca, Maria A; Martínez-Ricarte, Francisco-Ramon; Gándara, Dario F; Coscojuela, Pilar; Martínez-Sáez, Elena; Sahuquillo, Juan

2017-10-01

Stereotactic biopsy is a minimally invasive technique that allows brain tissue samples to be obtained with low risk. Classically, different techniques have been used to identify the biopsy site after surgery. To describe a technique to identify the precise location of the target in the postoperative CT scan using the injection of a low volume of air into the biopsy cannula. Seventy-five biopsies were performed in 65 adults and 10 children (40 males and 35 females, median age 51 years). Frame-based biopsy was performed in 46 patients, while frameless biopsy was performed in the remaining 29 patients. In both systems, after brain specimens had been collected and with the biopsy needle tip in the center of the target, a small volume of air (median 0.7 cm 3 ) was injected into the site. A follow-up CT scan was performed in all patients. Intracranial air in the selected target was present in 69 patients (92%). No air was observed in two patients (air volume administered in these 2 cases was below 0.7 cm 3 ), while in the remaining four patients blood content was observed in the target. The diagnostic yield in this series was 97.3%. No complications were found to be associated with intracranial air injection in any of the 75 patients who underwent this procedure. The air-injection maneuver proposed for use in stereotactic biopsies of intracranial mass lesions is a safe and reliable technique that allows the exact biopsy site to be located without any related complications.

Real time magnetic resonance guided endomyocardial local delivery

PubMed Central

Corti, R; Badimon, J; Mizsei, G; Macaluso, F; Lee, M; Licato, P; Viles-Gonzalez, J F; Fuster, V; Sherman, W

2005-01-01

Objective: To investigate the feasibility of targeting various areas of left ventricle myocardium under real time magnetic resonance (MR) imaging with a customised injection catheter equipped with a miniaturised coil. Design: A needle injection catheter with a mounted resonant solenoid circuit (coil) at its tip was designed and constructed. A 1.5 T MR scanner with customised real time sequence combined with in-room scan running capabilities was used. With this system, various myocardial areas within the left ventricle were targeted and injected with a gadolinium-diethylenetriaminepentaacetic acid (DTPA) and Indian ink mixture. Results: Real time sequencing at 10 frames/s allowed clear visualisation of the moving catheter and its transit through the aorta into the ventricle, as well as targeting of all ventricle wall segments without further image enhancement techniques. All injections were visualised by real time MR imaging and verified by gross pathology. Conclusion: The tracking device allowed real time in vivo visualisation of catheters in the aorta and left ventricle as well as precise targeting of myocardial areas. The use of this real time catheter tracking may enable precise and adequate delivery of agents for tissue regeneration. PMID:15710717

Risk Factors Associated with Unsafe Injection Practices at the First Injection Episode among Intravenous Drug Users in France: Results from PrimInject, an Internet Survey

PubMed Central

Guignard, Romain; Lert, France; Roy, Elise

2015-01-01

Background. New drug use patterns may increase the risk of human immunodeficiency virus and hepatitis infections. In France, new injection patterns among youths with diverse social backgrounds have emerged, which may explain the persistently high rates of hepatitis C virus infection. This study explores factors associated with injection risk behaviours at first injection among users who began injecting in the post-2000 era. Methods. A cross-sectional study was conducted on the Internet from October 2010 to March 2011, through an online questionnaire. Multivariate logistic regression identified the independent correlates of needle sharing and equipment (cooker/cotton filter) sharing. Results. Among the 262 respondents (mean age 25 years), 65% were male. Both risk behaviours were positively associated with initiation before 18 years of age (aOR 3.7 CI 95% 1.3–10.6 and aOR 3.0 CI 95% 1.3–7.0) and being injected by another person (aOR 3.1 CI 95% 1.0–9.9 and aOR 3.0 CI 95% 1.3–7.1). Initiation at a party was an independent correlate of equipment sharing (aOR 2.6 95% CI 1.0–6.8). Conclusions. Results suggest a need for innovative harm reduction programmes targeting a variety of settings and populations, including youths and diverse party scenes. Education of current injectors to protect both themselves and those they might initiate into injection is critically important. PMID:26504609

Advanced cell therapies: targeting, tracking and actuation of cells with magnetic particles.

PubMed

Connell, John J; Patrick, P Stephen; Yu, Yichao; Lythgoe, Mark F; Kalber, Tammy L

2015-01-01

Regenerative medicine would greatly benefit from a new platform technology that enabled measurable, controllable and targeting of stem cells to a site of disease or injury in the body. Superparamagnetic iron-oxide nanoparticles offer attractive possibilities in biomedicine and can be incorporated into cells, affording a safe and reliable means of tagging. This review describes three current and emerging methods to enhance regenerative medicine using magnetic particles to guide therapeutic cells to a target organ; track the cells using MRI and assess their spatial localization with high precision and influence the behavior of the cell using magnetic actuation. This approach is complementary to the systemic injection of cell therapies, thus expanding the horizon of stem cell therapeutics.

Photoacoustic imaging of tumor targeting with biotin conjugated nanostructured phthalocyanine assemblies

NASA Astrophysics Data System (ADS)

Lee, Seunghyun; Li, Xingshu; Lee, Dayoung; Yoon, Juyoung; Kim, Chulhong

2018-02-01

Visualizing biological markers and delivering bioactive agents to living organisms are important to biological research. In recent decades, photoacoustic imaging (PAI) has been significantly improved in the area of molecular imaging, which provides high-resolution volume imaging with high optical absorption contrast. To demonstrate the ability of nanoprobes to target tumors using PAI, we synthesize convertible nanostructured agents with strong photothermal and photoacoustic properties and linked the nanoprobe with biotin to target tumors in small animal model. Interestingly, these nanoprobes allow partial to disassemble in the presence of targeted proteins that switchable photoactivity, thus the nanoprobes provides a fluorescent-cancer imaging with high signal-to-background ratios. The proposed nanoprobe produce a much stronger PA signal compared to the same concentration of methylene blue (MB), which is widely used in clinical study and contrast agent for PAI. The biotin conjugated nanoprobe has high selectivity for biotin receptor positive cancer cells such as A549 (human lung cancer). Then we subsequently examined the PA properties of the nanoprobe that are inherently suitable for in vivo PAI. After injecting of the nanoprobe via intravenous method, we observed the mice's whole body by PA imaging and acquired the PA signal near the cancer. The PA signal increased linearly with time after injection and the fluorescence signal near the cancer was confirmed by fluorescence imaging. The ability to target a specific cancer of the nanoprobe was well verified by PA imaging. This study provides valuable perspective on the advancement of clinical translations and in the design of tumor-targeting phototheranostic agents that could act as new nanomedicines.

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

Transcranial Electrical Neuromodulation Based on the Reciprocity Principle

PubMed Central

Fernández-Corazza, Mariano; Turovets, Sergei; Luu, Phan; Anderson, Erik; Tucker, Don

2016-01-01

A key challenge in multi-electrode transcranial electrical stimulation (TES) or transcranial direct current stimulation (tDCS) is to find a current injection pattern that delivers the necessary current density at a target and minimizes it in the rest of the head, which is mathematically modeled as an optimization problem. Such an optimization with the Least Squares (LS) or Linearly Constrained Minimum Variance (LCMV) algorithms is generally computationally expensive and requires multiple independent current sources. Based on the reciprocity principle in electroencephalography (EEG) and TES, it could be possible to find the optimal TES patterns quickly whenever the solution of the forward EEG problem is available for a brain region of interest. Here, we investigate the reciprocity principle as a guideline for finding optimal current injection patterns in TES that comply with safety constraints. We define four different trial cortical targets in a detailed seven-tissue finite element head model, and analyze the performance of the reciprocity family of TES methods in terms of electrode density, targeting error, focality, intensity, and directionality using the LS and LCMV solutions as the reference standards. It is found that the reciprocity algorithms show good performance comparable to the LCMV and LS solutions. Comparing the 128 and 256 electrode cases, we found that use of greater electrode density improves focality, directionality, and intensity parameters. The results show that reciprocity principle can be used to quickly determine optimal current injection patterns in TES and help to simplify TES protocols that are consistent with hardware and software availability and with safety constraints. PMID:27303311

Transcranial Electrical Neuromodulation Based on the Reciprocity Principle.

PubMed

Fernández-Corazza, Mariano; Turovets, Sergei; Luu, Phan; Anderson, Erik; Tucker, Don

2016-01-01

A key challenge in multi-electrode transcranial electrical stimulation (TES) or transcranial direct current stimulation (tDCS) is to find a current injection pattern that delivers the necessary current density at a target and minimizes it in the rest of the head, which is mathematically modeled as an optimization problem. Such an optimization with the Least Squares (LS) or Linearly Constrained Minimum Variance (LCMV) algorithms is generally computationally expensive and requires multiple independent current sources. Based on the reciprocity principle in electroencephalography (EEG) and TES, it could be possible to find the optimal TES patterns quickly whenever the solution of the forward EEG problem is available for a brain region of interest. Here, we investigate the reciprocity principle as a guideline for finding optimal current injection patterns in TES that comply with safety constraints. We define four different trial cortical targets in a detailed seven-tissue finite element head model, and analyze the performance of the reciprocity family of TES methods in terms of electrode density, targeting error, focality, intensity, and directionality using the LS and LCMV solutions as the reference standards. It is found that the reciprocity algorithms show good performance comparable to the LCMV and LS solutions. Comparing the 128 and 256 electrode cases, we found that use of greater electrode density improves focality, directionality, and intensity parameters. The results show that reciprocity principle can be used to quickly determine optimal current injection patterns in TES and help to simplify TES protocols that are consistent with hardware and software availability and with safety constraints.

Nanobubbles as ultrasound contrast agent for facilitating small cell lung cancer imaging

PubMed Central

Wang, Jin-Ping; Zhou, Xiao-Lin; Yan, Ji-Ping; Zheng, Rong-Qin; Wang, Wei

2017-01-01

Background This study is to investigate whether liposome-loaded nanobubbles (NBs) have the potentials to carry anti-pro-gastrin releasing peptide (proGRP) antibody and enhance ultrasound imaging of small cell lung cancer (SCLC). Methods NBs were loaded with an antibody against SCLC (H446 cell line). A nude mouse model of SCLC tumor was established by a subcutaneous injection of tumor cell suspension in the dorsal skin. Images for contrast-enhanced ultrasound (CEUS) of xenograft tumors in the model were obtained through an intravenous injection of blank and targeting NBs. Results The targeted NBs showed a high binding affinity (90.2 ± 3.24%) of the H446 cells in vitro as compared to the blank NBs that have no affinity of the cells. In process of tumor imaging, no mice died of the NB application. CEUS imaging of the targeted NBs manifested significant increases in half-peak time, area under the curve and peak intensity as compared to the blank NBs. In the model of SCLC, treatment with targeting NBs resulted in a large amount of fluorescent dye accumulated in the tumor tissue but not the liver tissue. Conclusion Our results indicate that NBs can carry antibody traveling to the SCLC cells, whereas application of NBs is safe and reliable in serving as ultrasound contrast agents for improving SCLC imaging. PMID:29100457

Electromicroinjection of particles into living cells

DOEpatents

Ray, F. Andrew; Cram, L. Scott; Galey, William R.

1988-01-01

Method and apparatus for introducing particles into living cells. Fluorescently-stained human chromosomes are introduced into cultured, mitotic Chinese hamster cells using electromicroinjection. The recipient cells frequently survived the physiological perturbation imposed by a successful chromosome injection. Successfully injected recipient cells maintained viability as evidenced by their ability to be expanded. The technique relies on the surface charge of fluorescently stained chromosomes and their ability to be attracted and repelled to and from the tip of a micropipette. The apparatus includes a micropipette having a tip suitable for piercing the membrane of a target cell and an electrode inserted into the lumen thereof. The target cells and suspended particles are located in an electrically conducted solution, and the lumen of the micropipette is filled with an electrically conducting solution which contacts the electrode located therein. A second electrode is also located in the conducting solution containing the target cells and particles. Voltages applied to the electrode within the micropipette attract the particles to the region of the tip thereof. The particles adhere to the surface of the micropipette with sufficient force that insertion of the micropipette tip and attached particle through the membrane of a target cell will not dislodge the particle. By applying a voltage having the opposite polarity of the attraction voltage, the particles are expelled from the micropipette to which is then withdrawn from the cell body.

Longitudinal analysis of change in individual-level needle and syringe coverage amongst a cohort of people who inject drugs in Melbourne, Australia.

PubMed

O'Keefe, Daniel; Scott, Nick; Aitken, Campbell; Dietze, Paul

2017-07-01

Needle and syringe program (NSP) coverage is often calculated at the individual level. This method relates sterile needle and syringe acquisition to injecting frequency, resulting in a percentage of injecting episodes that utilise a sterile syringe. Most previous research using this method was restricted by their cross-sectional design, calling for longitudinal exploration of coverage. We used the data of 518 participants from an ongoing cohort of people who inject drugs in Melbourne, Australia. We calculated individual-level syringe coverage for the two weeks prior to each interview, then dichotomised the outcome as either "sufficient" (≥100% of injecting episodes covered by at least one reported sterile syringe) or "insufficient" (<100%). Time-variant predictors of change in recent coverage (from sufficient to insufficient coverage) were estimated longitudinally using logistic regression with fixed effects for each participant. Transitioning to methamphetamine injection (AOR:2.16, p=0.004) and a newly positive HCV RNA test result (AOR:4.93, p=0.001) were both associated with increased odds of change to insufficient coverage, whilst change to utilising NSPs as the primary source of syringe acquisition (AOR: 0.41, p=0.003) and opioid substitution therapy (OST) enrolment (AOR:0.51, p=0.013) were protective against a change to insufficient coverage. We statistically tested the transitions between time-variant exposure sub-groups and transitions in individual-level syringe coverage. Our results give important insights into means of improving coverage at the individual level, suggesting that methamphetamine injectors should be targeted, whilst both OST prescription and NSP should be expanded. Copyright © 2017 Elsevier B.V. All rights reserved.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

PubMed Central

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2014-01-01

Object Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. Methods In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Results Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. Conclusions This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures. PMID:24010975

Application of a real-time, calculable limiting form of the Renyi entropy for molecular imaging of tumors.

PubMed

Marsh, Jon N; Wallace, Kirk D; McCarthy, John E; Wickerhauser, Mladen V; Maurizi, Brian N; Lanza, Gregory M; Wickline, Samuel A; Hughes, Michael S

2010-08-01

Previously, we reported new methods for ultrasound signal characterization using entropy, H(f); a generalized entropy, the Renyi entropy, I(f)(r); and a limiting form of Renyi entropy suitable for real-time calculation, I(f),(infinity). All of these quantities demonstrated significantly more sensitivity to subtle changes in scattering architecture than energy-based methods in certain settings. In this study, the real-time calculable limit of the Renyi entropy, I(f),(infinity), is applied for the imaging of angiogenic murine neovasculature in a breast cancer xenograft using a targeted contrast agent. It is shown that this approach may be used to reliably detect the accumulation of targeted nanoparticles at five minutes post-injection in this in vivo model.

The effect on cadaver blood DNA identification by the use of targeted and whole body post-mortem computed tomography angiography.

PubMed

Rutty, Guy N; Barber, Jade; Amoroso, Jasmin; Morgan, Bruno; Graham, Eleanor A M

2013-12-01

Post-mortem computed tomography angiography (PMCTA) involves the injection of contrast agents. This could have both a dilution effect on biological fluid samples and could affect subsequent post-contrast analytical laboratory processes. We undertook a small sample study of 10 targeted and 10 whole body PMCTA cases to consider whether or not these two methods of PMCTA could affect post-PMCTA cadaver blood based DNA identification. We used standard methodology to examine DNA from blood samples obtained before and after the PMCTA procedure. We illustrate that neither of these PMCTA methods had an effect on the alleles called following short tandem repeat based DNA profiling, and therefore the ability to undertake post-PMCTA blood based DNA identification.

Targeted, noninvasive blockade of cortical neuronal activity

NASA Astrophysics Data System (ADS)

McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

2015-11-01

Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1-5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

Time Reversed Electromagnetics as a Novel Method for Wireless Power Transfer

NASA Astrophysics Data System (ADS)

Challa, Anu; Anlage, Steven M.; Tesla Team

Taking advantage of ray-chaotic enclosures, time reversal has been shown to securely transmit information via short-wavelength waves between two points, yielding noise at all other sites. In this presentation, we propose a method to adapt the signal-focusing technique to electromagnetic signals in order to transmit energy to portable devices. Relying only on the time-reversal invariance properties of waves, the technique is unencumbered by the inversely-proportional-to-distance path loss or precise orientation requirements of its predecessors, making it attractive for power transfer applications. We inject a short microwave pulse into a complex, wave-chaotic chamber and collect the resulting long time-domain signal at a designated transceiver. The signal is then time reversed and emitted from the collection site, collapsing as a time-reversed replica of the initial pulse at the injection site. When amplified, this reconstruction is robust, as measured through metrics of peak-to-peak voltage and energy transfer ratio. We experimentally demonstrate that time reversed collapse can be made on a moving target, and propose a way to selectively target devices through nonlinear time-reversal. University of Maryland Gemstone Team TESLA: Frank Cangialosi, Anu Challa, Tim Furman, Tyler Grover, Patrick Healey, Ben Philip, Brett Potter, Scott Roman, Andrew Simon, Liangcheng Tao, Alex Tabatabai.

Trace analysis of pesticides in paddy field water by direct injection using liquid chromatography-quadrupole-linear ion trap-mass spectrometry.

PubMed

Pareja, Lucía; Martínez-Bueno, M J; Cesio, Verónica; Heinzen, Horacio; Fernández-Alba, A R

2011-07-29

A multiresidue method was developed for the quantification and confirmation of 70 pesticides in paddy field water. After its filtration, water was injected directly in a liquid chromatograph coupled to a hybrid triple quadrupole-linear ion trap-mass spectrometer (QqLIT). The list of target analytes included organophosphates, phenylureas, sulfonylureas, carbamates, conazoles, imidazolinones and others compounds widely used in different countries where rice is cropped. Detection and quantification limits achieved were in the range from 0.4 to 80 ng L(-1) and from 2 to 150 ng L(-1), respectively. Correlation coefficients for the calibration curves in the range 0.1-50 μg L(-1) were higher than 0.99 except for diazinon (0.1-25 μg L(-1)). Only 9 pesticides presented more than 20% of signal suppression/enhancement, no matrix effect was observed in the studied conditions for the rest of the target pesticides. The method developed was used to investigate the occurrence of pesticides in 59 water samples collected in paddy fields located in Spain and Uruguay. The study shows the presence of bensulfuron methyl, tricyclazole, carbendazim, imidacloprid, tebuconazole and quinclorac in a concentration range from 0.08 to 7.20 μg L(-1). Copyright © 2011 Elsevier B.V. All rights reserved.

A Multi-institutional Clinical Trial of Rectal Dose Reduction via Injected Polyethylene-Glycol Hydrogel During Intensity Modulated Radiation Therapy for Prostate Cancer: Analysis of Dosimetric Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Danny Y., E-mail: dsong2@jhmi.edu; Herfarth, Klaus K.; Uhl, Matthias

2013-09-01

Purpose: To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiation therapy for prostate cancer and to assess for factors correlated with rectal dose reduction. Methods and Materials: Fifty-two patients at 4 institutions were enrolled into a prospective pilot clinical trial. Patients underwent baseline scans and then were injected with perirectal spacing hydrogel and rescanned. Intensity modulated radiation therapy plans were created on both scans for comparison. The objectives were to establish rates of creation of ≥7.5 mm of prostate-rectal separation, and decrease in rectal V70 of ≥25%. Multiple regression analysis was performed tomore » evaluate the associations between preinjection and postinjection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, planning target volume (PTV), and postinjection midgland separation, gel volume, gel thickness, length of PTV/gel contact, and gel left-to-right symmetry. Results: Hydrogel resulted in ≥7.5-mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of ≥25%, with a mean reduction of 8.0 Gy. There were no significant differences in preinjection and postinjection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different before versus after injection (P=.02); plans with worse conformity indexes after injection compared with before injection (n=13) still had improvements in rectal V70. In multiple regression analysis, greater postinjection reduction in V70 was associated with decreased relative postinjection plan conformity (P=.01). Reductions in V70 did not significantly vary by institution, despite significant interinstitutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. Conclusions: Injection of hydrogel into the prostate-rectal interface resulted in dose reductions to rectum for >90% of patients treated. Rectal sparing was statistically significant across a range of 10 to 75 Gy and was demonstrated within the presence of significant interinstitutional variability in plan conformity, target definitions, and injection results.« less

The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos.

PubMed

Miyamoto, Kei; Suzuki, Ken-Ichi T; Suzuki, Miyuki; Sakane, Yuto; Sakuma, Tetsushi; Herberg, Sarah; Simeone, Angela; Simpson, David; Jullien, Jerome; Yamamoto, Takashi; Gurdon, J B

2015-01-01

Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0) needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN) mRNA to oocytes at the germinal vesicle (GV) stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders.

The spatial learning and memory performance in methamphetamine–sensitized and withdrawn rats

PubMed Central

Bigdeli, Imanollah; Asia, Masomeh Nikfarjam- Haft; Miladi-Gorji, Hossein; Fadaei, Atefeh

2015-01-01

Objective(s): There is controversial evidence about the effect of methamphetamine (METH) on spatial memory. We tested the time- dependent effects of METH on spatial short-term (working) and long-term (reference) memory in METH –sensitized and withdrawn rats in the Morris water maze. Materials and Methods: Rats were sensitized to METH (2 mg/kg, daily/5 days, SC). Rats were trained in water maze (4 trials/day/for 5 days). Probe test was performed 24 hr after training. Two days after probe test, working memory training (2 trials/day/for 5 days) was conducted. Acquisition–retention interval was 75 min. The treatment was continued per day 30 and 120 min before the test. Two groups of METH –sensitized rats were trained in reference memory after a longer period of withdrawal (30 days). Results: Sensitized rats exhibited significantly longer escape latencies on the training, spent significantly less time in the target zone (all, P<0.05), and their working memory impaired 30 min after injection. While, METH has no effect on the spatial learning process 120 min after injection, and rats spent significantly less time in the target zone (P<0.05), as well it has no effect on working memory. Also, impairment of reference memory persisted after prolonged abstinence. Conclusion: Our findings indicated that METH impaired spatial learning and memory 30 min after injection, but spared spatial learning, either acquisition or retention of spatial working, but partially impaired retention of spatial reference memory following 120 min after injection in sensitized rats, which persisted even after prolonged abstinence. PMID:25945235

Development of an injectable PHBV microparticles-GG hydrogel hybrid system for regenerative medicine.

PubMed

Pacheco, Daniela P; Amaral, Maria H; Reis, Rui L; Marques, Alexandra P; Correlo, Vítor M

2015-01-15

Uncontrollable displacements that greatly affect the concentration of active agents at the target tissues are among a major limitation of the use of microparticulate drug delivery systems (DDS). Under this context a biphasic injectable DDS combining poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles (MPs) and a gellan gum (GG) injectable hydrogel is herein proposed for the localized delivery and long-term retention of MPs carrying hydrophilic and hydrophobic model active agents. A double emulsion-solvent evaporation method was adopted to develop the PHBV MPs, carrying bovine serum albumin (BSA) or dexamethasone (Dex) as hydrophilic and hydrophobic active agents' models, respectively. Moreover, this method was modified, together with the properties of the hydrogel to tailor the delivery profile of the active agents. Variations of the composition of the organic phase during the process allowed tuning surface topography, particle size distribution and core porosity of the PHBV MPs and, thus, the in vitro release profile of Dex but not of BSA. Besides, after embedding hydrogels of higher GG concentration led to a slower and more sustained release of both active agents, independently of the processing conditions of the microparticulate system. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimization of Injection Molding Parameters for HDPE/TiO₂ Nanocomposites Fabrication with Multiple Performance Characteristics Using the Taguchi Method and Grey Relational Analysis.

PubMed

Pervez, Hifsa; Mozumder, Mohammad S; Mourad, Abdel-Hamid I

2016-08-22

The current study presents an investigation on the optimization of injection molding parameters of HDPE/TiO₂ nanocomposites using grey relational analysis with the Taguchi method. Four control factors, including filler concentration (i.e., TiO₂), barrel temperature, residence time and holding time, were chosen at three different levels of each. Mechanical properties, such as yield strength, Young's modulus and elongation, were selected as the performance targets. Nine experimental runs were carried out based on the Taguchi L₉ orthogonal array, and the data were processed according to the grey relational steps. The optimal process parameters were found based on the average responses of the grey relational grades, and the ideal operating conditions were found to be a filler concentration of 5 wt % TiO₂, a barrel temperature of 225 °C, a residence time of 30 min and a holding time of 20 s. Moreover, analysis of variance (ANOVA) has also been applied to identify the most significant factor, and the percentage of TiO₂ nanoparticles was found to have the most significant effect on the properties of the HDPE/TiO₂ nanocomposites fabricated through the injection molding process.

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma

PubMed Central

Ge, Yaoqi; Zhong, Yuejiao; Ji, Guozhong; Lu, Qianling; Dai, Xinyu; Guo, Zhirui; Zhang, Peng; Peng, Gang; Zhang, Kangzhen; Li, Yuntao

2018-01-01

Objective To study the characterization of Fe3O4@Au-C225 composite targeted MNPs. Methods Fe3O4@Au-C225 was prepared by the absorption method. The immunosorbent assay was used to evaluate its absorption efficiency at C225 Fc. ZETA SIZER3000 laser particle size analyzer, ultraviolet photometer and its characteristics were analyzed by VSM. the targeting effect of Fe3O4@Au-C225 composite targeted MNPs on U251 cells in vitro were detected by 7.0 Tesla Micro-MR; and subcutaneous transplanted human glioma in nude mice were performed the targeting effect in vivo after tail vein injection of Fe3O4@Au-C225 composite targeted MNPs by MRI. Results The self-prepared Fe3O4@Au composite MNPs can adsorb C225 with high efficiency of adsorption so that Fe3O4@Au-C225 composite targeted MNPs were prepared successfully. Fe3O4@Au-C225 composite targeted MNPs favorably targeted human glioma cell line U251 in vitro; Fe3O4@Au-C225 composite targeted MNPs have good targeting ability to xenografted glioma on nude mice in vivo, and can be traced by MRI. Conclusion The Fe3O4@Au-C225 composite targeted MNPs have the potential to be used as a tracer for glioma in vivo. PMID:29652919

[Onyx embolization for treatment of dural arteriovenous fistula: comparison of long- distance versus routine injection method].

PubMed

He, Xiao-Yan; Zhang, Guo-Zhong; Li, Ming-Zhou; Wang, Gang; Liu, Dan; Qi, Song-Tao; Li, Wei-Guang; Feng, Wen-Feng

2016-03-01

To compare the efficacy, clinical characteristics, safety, injection time and radiation exposure of Onyx embolization using a long-distance injection method and routine injection method for management of dural arteriovenous fistula (DAVF). The clinical data were retrospectively analyzed in 59 patients with DAVF treated with Onyx embolization using long-distance injection method (28 patients) and routine injection method (31 patients). The efficacy, safety, injection time and radiation exposure during Onyx embolization were compared between the two injections methods. The average radiation dose exposure to the surgeon per procedure was significantly lower in the long-distance injection group than in the routine group. The injection time (P=0.53), injection volume (P=0.78), number of supply arteries (P=0.80), Cognard types (P=0.67), and effect of embolization (P=0.88) were all similar between the two groups. Endovaseular treatment of intracranial DAVF with Onyx embolization using the long-distance injection method is feasible, safe and effective and can reduce the radiation exposure to the surgeon.

Single Event Analysis and Fault Injection Techniques Targeting Complex Designs Implemented in Xilinx-Virtex Family Field Programmable Gate Array (FPGA) Devices

NASA Technical Reports Server (NTRS)

Berg, Melanie D.; LaBel, Kenneth; Kim, Hak

2014-01-01

An informative session regarding SRAM FPGA basics. Presenting a framework for fault injection techniques applied to Xilinx Field Programmable Gate Arrays (FPGAs). Introduce an overlooked time component that illustrates fault injection is impractical for most real designs as a stand-alone characterization tool. Demonstrate procedures that benefit from fault injection error analysis.

SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery.

PubMed

Zha, Haihong; Cai, Yuping; Yin, Yandong; Wang, Zhuozhong; Li, Kang; Zhu, Zheng-Jiang

2018-03-20

The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS 2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).

Rapid screening and identification of chemical hazards in surface and drinking water using high resolution mass spectrometry and a case-control filter.

PubMed

Kaserzon, Sarit L; Heffernan, Amy L; Thompson, Kristie; Mueller, Jochen F; Gomez Ramos, Maria Jose

2017-09-01

Access to clean, safe drinking water poses a serious challenge to regulators, and requires analytical strategies capable of rapid screening and identification of potentially hazardous chemicals, specifically in situations when threats to water quality or security require rapid investigations and potential response. This study describes a fast and efficient chemical hazard screening strategy for characterising trace levels of polar organic contaminants in water matrices, based on liquid chromatography high resolution mass spectrometry with post-acquisition 'case-control' data processing. This method allowed for a rapid response time of less than 24 h for the screening of target, suspect and non-target unknown chemicals via direct injection analysis, and a second, more sensitive analysis option requiring sample pre-concentration. The method was validated by fortifying samples with a range of pesticides, pharmaceuticals and personal care products (n = 46); with >90% of target compounds positively screened in samples at 1 ng mL -1 , and 46% at 0.1 ng mL -1 when analysed via direct injection. To simulate a contamination event samples were fortified with compounds not present in the commercial library (designated 'non-target compounds'; fipronil and fenitrothion), tentatively identified at 0.2 and 1 ng mL -1 , respectively; and a compound not included in any known commercial library or public database (designated 'unknown' compounds; 8Cl - perfluorooctanesulfonic acid), at 0.8 ng mL -1 . The method was applied to two 'real-case' scenarios: (1) the assessment of drinking water safety during a high-profile event in Brisbane, Australia; and (2) to screen treated, re-circulated drinking water and pre-treated (raw) water. The validated workflow was effective for rapid prioritisation and screening of suspect and non-target potential hazards at trace levels, and could be applied to a wide range of matrices and investigations where comparison of organic contaminants between an affected and control site and or timeframe is warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Porous media heat transfer for injection molding

DOEpatents

Beer, Neil Reginald

2016-05-31

The cooling of injection molded plastic is targeted. Coolant flows into a porous medium disposed within an injection molding component via a porous medium inlet. The porous medium is thermally coupled to a mold cavity configured to receive injected liquid plastic. The porous medium beneficially allows for an increased rate of heat transfer from the injected liquid plastic to the coolant and provides additional structural support over a hollow cooling well. When the temperature of the injected liquid plastic falls below a solidifying temperature threshold, the molded component is ejected and collected.

High resolution 3D MRI of mouse mammary glands with intra-ductal injection of contrast media

PubMed Central

Markiewicz, Erica; Fan, Xiaobing; Mustafi, Devkumar; Zamora, Marta; Roman, Brian B.; Jansen, Sanaz A.; Macleod, Kay; Conzen, Suzanne D.; Karczmar, Gregory S.

2014-01-01

The purpose of this study was to use high resolution 3D MRI to study mouse mammary gland ductal architecture based on intra-ductal injection of contrast agents. Female FVB/N mice age 12–20 weeks (n = 12), were used in this study. A 34G, 45° tip Hamilton needle with a 25uL Hamilton syringe was inserted into the tip of the nipple. Approximately 20–25uL of a Gadodiamide/Trypan blue/saline solution was injected slowly over one minute into the nipple and duct. To prevent washout of contrast media from ducts due to perfusion, and maximize the conspicuity of ducts on MRI, mice were sacrificed one minute after injection. High resolution 3D T1-weighted images were acquired on a 9.4T Bruker scanner after sacrifice to eliminate motion artifacts and reduce contrast media leakage from ducts. Trypan blue staining was well distributed throughout the ductal tree. MRI showed the mammary gland ductal structure clearly. In spoiled gradient echo T1-weighted images, the signal-to-noise ratio of regions identified as enhancing mammary ducts following contrast injection was significantly higher than that of muscle (p < 0.02) and significantly higher than that of contralateral mammary ducts that were not injected with contrast media (p < 0.0001). The methods described here could be adapted for injection of specialized contrast agents to measure metabolism or target receptors in normal ducts and ducts with in situ cancers. PMID:25179139

Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

NASA Astrophysics Data System (ADS)

Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

2016-01-01

Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

Non-fatal overdose among adult prisoners with a history of injecting drug use in two Australian states.

PubMed

Moore, Elizabeth; Winter, Rebecca; Indig, Devon; Greenberg, David; Kinner, Stuart A

2013-11-01

Recently released prisoners are at markedly increased risk of death and drug-related causes predominate. Non-fatal overdose (NFOD) is considerably more common than fatal overdose, but has received relatively little research attention and most studies of NFOD in this population have suffered from small samples of unknown representativeness. This study aimed to estimate the prevalence and correlates of lifetime NFOD among prisoners in NSW and Queensland. Cross-sectional surveys of adult prisoners in two Australian states: New South Wales (n=972) and Queensland (n=1316). Use of similar measures and methods in the two states made direct comparison of findings possible. In both NSW and Queensland, 23% of participants reported a lifetime history of NFOD and prisoners with a history of injecting drug use were significantly more likely to report lifetime NFOD. The lifetime prevalence of NFOD among prisoners with a history of injecting drug use was significantly higher in NSW than in Queensland (44% vs. 35%; p<0.01). Independent correlates of lifetime NFOD were similar across the two states and included ever attempting suicide, ever injecting heroin, and ever injecting opioids. The risk of NFOD among prisoners with a history of injecting drug use is high. An understanding of the risk factors for NFOD in this population can inform targeted, evidence-based interventions to reduce this risk. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Burst nucleation by hot injection for size controlled synthesis of ε-cobalt nanoparticles.

PubMed

Zacharaki, Eirini; Kalyva, Maria; Fjellvåg, Helmer; Sjåstad, Anja Olafsen

2016-01-01

Reproducible growth of narrow size distributed ε-Co nanoparticles with a specific size requires full understanding and identification of the role of essential synthesis parameters for the applied synthesis method. For the hot injection methodology, a significant discrepancy with respect to obtained sizes and applied reaction conditions is reported. Currently, a systematic investigation controlling key synthesis parameters as injection-temperature and time, metal to surfactant ratio and reaction holding time in terms of their impact on mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameter using dichlorobenzene (DCB), Co2(CO)8 and oleic acid (OA) as the reactant matrix is lacking. A series of solution-based ε-Co nanoparticles were synthesized using the hot injection method. Suspensions and obtained particles were analyzed by DLS, ICP-OES, (synchrotron)XRD and TEM. Rietveld refinements were used for structural analysis. Mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameters were calculated with basis in measurements of 250-500 particles for each synthesis. 95 % bias corrected confidence intervals using bootstrapping were calculated for syntheses with three or four replicas. ε-Co NPs in the size range ~4-10 nm with a narrow size distribution are obtained via the hot injection method, using OA as the sole surfactant. Typically the synthesis yield is ~75 %, and the particles form stable colloidal solutions when redispersed in hexane. Reproducibility of the adopted synthesis procedure on replicate syntheses was confirmed. We describe in detail the effects of essential synthesis parameters, such as injection-temperature and time, metal to surfactant ratio and reaction holding time in terms of their impact on mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameter. The described synthesis procedure towards ε-Co nanoparticles (NPs) is concluded to be robust when controlling key synthesis parameters, giving targeted particle diameters with a narrow size distribution. We have identified two major synthesis parameters which control particle size, i.e., the metal to surfactant molar ratio and the injection temperature of the hot OA-DCB solution into which the cobalt precursor is injected. By increasing the metal to surfactant molar ratio, the mean particle diameter of the ε-Co NPs has been found to increase. Furthermore, an increase in the injection temperature of the hot OA-DCB solution into which the cobalt precursor is injected, results in a decrease in the mean particle diameter of the ε-Co NPs, when the metal to surfactant molar ratio [Formula: see text] is fixed at ~12.9.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

PubMed

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Cryogenic hydrogen fuel for controlled inertial confinement fusion (formation of reactor-scale cryogenic targets)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aleksandrova, I. V.; Koresheva, E. R., E-mail: elena.koresheva@gmail.com; Krokhin, O. N.

2016-12-15

In inertial fusion energy research, considerable attention has recently been focused on low-cost fabrication of a large number of targets by developing a specialized layering module of repeatable operation. The targets must be free-standing, or unmounted. Therefore, the development of a target factory for inertial confinement fusion (ICF) is based on methods that can ensure a cost-effective target production with high repeatability. Minimization of the amount of tritium (i.e., minimization of time and space at all production stages) is a necessary condition as well. Additionally, the cryogenic hydrogen fuel inside the targets must have a structure (ultrafine layers—the grain sizemore » should be scaled back to the nanometer range) that supports the fuel layer survivability under target injection and transport through the reactor chamber. To meet the above requirements, significant progress has been made at the Lebedev Physical Institute (LPI) in the technology developed on the basis of rapid fuel layering inside moving free-standing targets (FST), also referred to as the FST layering method. Owing to the research carried out at LPI, unique experience has been gained in the development of the FST-layering module for target fabrication with an ultrafine fuel layer, including a reactor- scale target design. This experience can be used for the development of the next-generation FST-layering module for construction of a prototype of a target factory for power laser facilities and inertial fusion power plants.« less

Eos modeling and reservoir simulation study of bakken gas injection improved oil recovery in the elm coulee field, Montana

NASA Astrophysics Data System (ADS)

Pu, Wanli

The Bakken Formation in the Williston Basin is one of the most productive liquid-rich unconventional plays. The Bakken Formation is divided into three members, and the Middle Bakken Member is the primary target for horizontal wellbore landing and hydraulic fracturing because of its better rock properties. Even with this new technology, the primary recovery factor is believed to be only around 10%. This study is to evaluate various gas injection EOR methods to try to improve on that low recovery factor of 10%. In this study, the Elm Coulee Oil Field in the Williston Basin was selected as the area of interest. Static reservoir models featuring the rock property heterogeneity of the Middle Bakken Member were built, and fluid property models were built based on Bakken reservoir fluid sample PVT data. By employing both compositional model simulation and Todd-Longstaff solvent model simulation methods, miscible gas injections were simulated and the simulations speculated that oil recovery increased by 10% to 20% of OOIP in 30 years. The compositional simulations yielded lower oil recovery compared to the solvent model simulations. Compared to the homogeneous model, the reservoir model featuring rock property heterogeneity in the vertical direction resulted in slightly better oil recovery, but with earlier CO2 break-through and larger CO2 production, suggesting that rock property heterogeneity is an important property for modeling because it has a big effect on the simulation results. Long hydraulic fractures shortened CO2 break-through time greatly and increased CO 2 production. Water-alternating-gas injection schemes and injection-alternating-shut-in schemes can provide more options for gas injection EOR projects, especially for gas production management. Compared to CO2 injection, separator gas injection yielded slightly better oil recovery, meaning separator gas could be a good candidate for gas injection EOR; lean gas generated the worst results. Reservoir simulations also indicate that original rock properties are the dominant factor for the ultimate oil recovery for both primary recovery and gas injection EOR. Because reservoir simulations provide critical inputs for project planning and management, more effort needs to be invested into reservoir modeling and simulation, including building enhanced geologic models, fracture characterization and modeling, and history matching with field data. Gas injection EOR projects are integrated projects, and the viability of a project also depends on different economic conditions.

Targeted mutagenesis of aryl hydrocarbon receptor 2a and 2b genes in Atlantic killifish (Fundulus heteroclitus)

PubMed Central

Aluru, Neelakanteswar; Karchner, Sibel I.; Franks, Diana G.; Nacci, Diane; Champlin, Denise; Hahn, Mark E.

2014-01-01

Understanding molecular mechanisms of toxicity is facilitated by experimental manipulations, such as disruption of function by gene targeting, that are especially challenging in non-standard model species with limited genomic resources. While loss-of-function approaches have included gene knock-down using morpholino-modified oligonucleotides and random mutagenesis using mutagens or retroviruses, more recent approaches include targeted mutagenesis using zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. These latter methods provide more accessible opportunities to explore gene function in non-traditional model species. To facilitate evaluations of toxic mechanisms for important categories of aryl hydrocarbon pollutants, whose actions are known to be receptor mediated, we used ZFN and CRISPR-Cas9 approaches to generate aryl hydrocarbon receptor 2a (AHR2a) and AHR2b gene mutations in Atlantic killifish (Fundulus heteroclitus) embryos. This killifish is a particularly valuble non-traditional model for this study, with multiple paralogs of AHR whose functions are not well characterized. In addition, some populations of this species have evolved resistance to toxicants such as halogenated aromatic hydrocarbons. AHR-null killifish will be valuable for characterizing the role of the individual AHR paralogs in evolved resistance, as well as in normal development. We first used five-finger ZFNs targeting exons 1 and 3 of AHR2a. Subsequently, CRISPR-Cas9 guide RNAs were designed to target regions in exon 2 and 3 of AHR2a and AHR2b. We successfully induced frameshift mutations in AHR2a exon 3 with ZFN and CRISPR-Cas9 guide RNAs, with mutation frequencies of 10% and 16%, respectively. In AHR2b, mutations were induced using CRISPR-Cas9 guide RNAs targeting sites in both exon 2 (17%) and exon 3 (63%). We screened AHR2b exon 2 CRISPR-Cas9-injected embryos for off-target effects in AHR paralogs. No mutations were observed in closely related AHR genes (AHR1a, AHR1b, AHR2a, AHRR) in the CRISPR-Cas9-injected embryos. Overall, our results demonstrate that targeted genome-editing methods are efficient in inducing mutations at specific loci in embryos of a non-traditional model species, without detectable off-target effects in paralogous genes. PMID:25481785

Design strategies and applications of circulating cell-mediated drug delivery systems.

PubMed

Su, Yixue; Xie, Zhiwei; Kim, Gloria B; Dong, Cheng; Yang, Jian

2015-01-01

Drug delivery systems, particularly nanomaterial-based drug delivery systems, possess a tremendous amount of potential to improve diagnostic and therapeutic effects of drugs. Controlled drug delivery targeted to a specific disease is designed to significantly improve the pharmaceutical effects of drugs and reduce their side effects. Unfortunately, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even with the development of numerous surface markers and targeting modalities. Thus, alternative drug and nanomedicine targeting approaches are desired. Circulating cells, such as erythrocytes, leukocytes, and stem cells, present innate disease sensing and homing properties. Hence, using living cells as drug delivery carriers has gained increasing interest in recent years. This review highlights the recent advances in the design of cell-mediated drug delivery systems and targeting mechanisms. The approaches of drug encapsulation/conjugation to cell-carriers, cell-mediated targeting mechanisms, and the methods of controlled drug release are elaborated here. Cell-based "live" targeting and delivery could be used to facilitate a more specific, robust, and smart payload distribution for the next-generation drug delivery systems.

Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cancer

NASA Astrophysics Data System (ADS)

Chattopadhyay, Niladri

The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20--25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2-overexpressing tumor cells following i.t. injection, with a lower proportion of AuNPs redistributing to normal tissues. In vivo, the combination of HER-2 targeted AuNPs injected i.t. and X-radiation (11 Gy) yielded a 46% decrease in tumor size over a 4 month period in contrast to an 11.5% increase in tumor size for X-radiation treatment alone. Toxicology studies (evaluated through complete blood cell counts, by serum transaminase and creatinine measurements and by monitoring the body weight) demonstrated no apparent normal organ toxicity from the combination of HER-2 targeted AuNPs and X-radiation. These results are promising for the clinical translation of HER-2-targeted AuNPs for radiosensitization of tumors to X-radiation.

Intranasal administration of testosterone increased immobile-sniffing, exploratory behavior, motor behavior and grooming behavior in rats.

PubMed

Zhang, Guoliang; Shi, Geming; Tan, Huibing; Kang, Yunxiao; Cui, Huixian

2011-04-01

Currently, testosterone (T) replacement therapy is typically provided by oral medication, injectable T esters, surgically implanted T pellets, transdermal patches and gels. However, most of these methods of administration are still not ideal for targeting the central nervous system. Recently, therapeutic intranasal T administration (InT) has been considered as another option for delivering T to the brain. In the present study, the effects of 21-day InT treatment were assessed on open field behavior in gonadectomized (GDX) rats and intact rats. Subcutaneous injections of T at same dose were also tested in GDX rats. A total of 12 behavioral events were examined in GDX groups with or without T and in intact groups with or without InT. Significant decreases in open field activity were observed in rats after GDX without InT compared to sham-operated rats. The open field activity scores for most tests significantly increased with InT treatment in GDX rats and in intact rats compared with the corresponding GDX rats and intact rats. Intranasal administration of T improved the reduced behaviors resulted from T deficiency better than subcutaneous injection of T, demonstrating that T can be delivered to the brain by intranasal administration. Our results suggest that intranasal T delivery is an effective option for targeting the central nervous system. Copyright © 2011 Elsevier Inc. All rights reserved.

Spatial and temporal distribution of trunk-injected imidacloprid in apple tree canopies.

PubMed

Aćimović, Srđan G; VanWoerkom, Anthony H; Reeb, Pablo D; Vandervoort, Christine; Garavaglia, Thomas; Cregg, Bert M; Wise, John C

2014-11-01

Pesticide use in orchards creates drift-driven pesticide losses which contaminate the environment. Trunk injection of pesticides as a target-precise delivery system could greatly reduce pesticide losses. However, pesticide efficiency after trunk injection is associated with the underinvestigated spatial and temporal distribution of the pesticide within the tree crown. This study quantified the spatial and temporal distribution of trunk-injected imidacloprid within apple crowns after trunk injection using one, two, four or eight injection ports per tree. The spatial uniformity of imidacloprid distribution in apple crowns significantly increased with more injection ports. Four ports allowed uniform spatial distribution of imidacloprid in the crown. Uniform and non-uniform spatial distributions were established early and lasted throughout the experiment. The temporal distribution of imidacloprid was significantly non-uniform. Upper and lower crown positions did not significantly differ in compound concentration. Crown concentration patterns indicated that imidacloprid transport in the trunk occurred through radial diffusion and vertical uptake with a spiral pattern. By showing where and when a trunk-injected compound is distributed in the apple tree canopy, this study addresses a key knowledge gap in terms of explaining the efficiency of the compound in the crown. These findings allow the improvement of target-precise pesticide delivery for more sustainable tree-based agriculture. © 2014 Society of Chemical Industry.

Cavitational kyphoplasty: a new technique for reducing the rates of cement extravasation through targeted low-pressure cement injection.

PubMed

Mattei, Tobias A

2017-06-01

Previous studies have demonstrated lower rates of cement extravasation when comparing balloon kyphoplasty with vertebroplasty, an effect attributed to the low-pressure injection. However, in patients with isolated endplate fractures, balloon kyphoplasty may lead to further endplate damage and increased risks of intradiscal extravasation. The author provides a stepwise description of a new technique called cavitational kyphoplasty that allows targeted low-pressure cement injection without the necessity of balloon inflation. The new technique of cavitational kyphoplasty has been shown to be specially useful in patients with isolated endplate fractures without significant loss of the vertebral body height.

Methods for assisting recovery of damaged brain and spinal cord and treating various diseases using arrays of x-ray microplanar beams

DOEpatents

Dilmanian, F Avraham [Yaphank, NY; Anchel, David J [Rocky Point, NY; Gaudette, Glenn [Holden, MA; Romanelli, Pantaleo [Monteroduni, IT; Hainfeld, James [Shoreham, NY

2010-06-29

A method of assisting recovery of an injury site of the central nervous system (CNS) or treating a disease includes providing a therapeutic dose of X-ray radiation to a target volume through an array of parallel microplanar beams. The dose to treat CNS injury temporarily removes regeneration inhibitors from the irradiated site. Substantially unirradiated cells surviving between beams migrate to the in-beam portion and assist recovery. The dose may be staggered in fractions over sessions using angle-variable intersecting microbeam arrays (AVIMA). Additional doses are administered by varying the orientation of the beams. The method is enhanced by injecting stem cells into the injury site. One array or the AVIMA method is applied to ablate selected cells in a target volume associated with disease for palliative or curative effect. Atrial fibrillation is treated by irradiating the atrial wall to destroy myocardial cells while continuously rotating the subject.

Field Test of Enhanced Remedial Amendment Delivery Using a Shear-Thinning Fluid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Truex, Michael J.; Vermeul, Vincent R.; Adamson, David

2015-03-01

Heterogeneity of hydraulic properties in aquifers may lead to contaminants residing in lower-permeability zones where it is difficult to deliver remediation amendments using conventional injection processes. The focus of this effort is to examine use of a shear-thinning fluid (STF) to improve the uniformity of remedial amendment distribution within a heterogeneous aquifer. Previous studies have demonstrated the significant potential of STFs for improving remedial amendment delivery in heterogeneous aquifers, but quantitative evaluation of these improvements from field applications are lacking. A field-scale test was conducted that compares data from successive injection of a tracer in water followed by injection ofmore » a tracer in a STF to evaluate the impact of the STF on tracer distribution uniformity in the presence of permeability contrasts within the targeted injection zone. Data from tracer breakthrough at multiple depth-discrete monitoring intervals and electrical resistivity tomography showed that inclusion of STF in the injection solution slowed movement in high-permeability pathways, improved delivery of amendment to low-permeability materials, and resulted in better uniformity in injected fluid distribution within the targeted treatment zone.« less

Significance for secure CO2 storage of earthquakes induced by fluid injection

NASA Astrophysics Data System (ADS)

Verdon, James P.

2014-05-01

The link between subsurface fluid injection and induced seismicity has gained recent significance with an increase in earthquakes associated with the disposal of oilfield waste fluids. There are obvious similarities between wastewater reinjection and proposed CO2 storage (CCS) operations. However, as well as the seismic hazard, induced seismicity during CCS operations poses additional risks, because an induced event located above the target reservoir could compromise the hydraulic integrity of the caprock. In this paper we re-examine case examples where earthquakes have been induced by wastewater injection into deep aquifers in the light of proposed future CCS operations. In particular we consider possible controls on event magnitudes, and look at the spatial distributions of events. We find that the majority of events are located below the target reservoirs. This is an encouraging observation from the perspective of caprock integrity, although it presents a challenge in terms of pre-injection characterization of deep-lying faults several kilometres below the target zone. We observe that 99% of events are found within 20 km of injection wells, suggesting a minimum radius for geomechanical characterization and monitoring. We conclude by making recommendations for modelling and monitoring strategies to be followed prior to and during commercial-scale deployment of CO2 storage projects.

Development of a Postcolumn Infused-Internal Standard Liquid Chromatography Mass Spectrometry Method for Quantitative Metabolomics Studies.

PubMed

Liao, Hsiao-Wei; Chen, Guan-Yuan; Wu, Ming-Shiang; Liao, Wei-Chih; Lin, Ching-Hung; Kuo, Ching-Hua

2017-02-03

Quantitative metabolomics has become much more important in clinical research in recent years. Individual differences in matrix effects (MEs) and the injection order effect are two major factors that reduce the quantification accuracy in liquid chromatography-electrospray ionization-mass spectrometry-based (LC-ESI-MS) metabolomics studies. This study proposed a postcolumn infused-internal standard (PCI-IS) combined with a matrix normalization factor (MNF) strategy to improve the analytical accuracy of quantitative metabolomics. The PCI-IS combined with the MNF method was applied for a targeted metabolomics study of amino acids (AAs). D8-Phenylalanine was used as the PCI-IS, and it was postcolumn-infused into the ESI interface for calibration purposes. The MNF was used to bridge the AA response in a standard solution with the plasma samples. The MEs caused signal changes that were corrected by dividing the AA signal intensities by the PCI-IS intensities after adjustment with the MNF. After the method validation, we evaluated the method applicability for breast cancer research using 100 plasma samples. The quantification results revealed that the 11 tested AAs exhibit an accuracy between 88.2 and 110.7%. The principal component analysis score plot revealed that the injection order effect can be successfully removed, and most of the within-group variation of the tested AAs decreased after the PCI-IS correction. Finally, targeted metabolomics studies on the AAs showed that tryptophan was expressed more in malignant patients than in the benign group. We anticipate that a similar approach can be applied to other endogenous metabolites to facilitate quantitative metabolomics studies.

Establishing a rat model of spastic cerebral palsy by targeted ethanol injection

PubMed Central

Yu, Yadong; Li, Liang; Shao, Xinzhong; Tian, Fangtao; Sun, Qinglu

2013-01-01

Spastic cerebral palsy is generally considered to result from cerebral cortical or pyramidal tract damage. Here, we precisely targeted the left pyramidal tract of 2-month-old Sprague-Dawley rats placed on a stereotaxic instrument under intraperitoneal anesthesia. Based on the rat brain stereotaxic map, a 1-mm hole was made 10 mm posterior to bregma and 0.8 mm left of sagittal suture. A microsyringe was inserted perpendicularly to the surface of the brain to a depth of 9.7 mm, and 15 μL of ethanol was slowly injected to establish a rat model of spastic cerebral palsy. After modeling, the rats appeared to have necrotic voids in the pyramidal tract and exhibited typical signs and symptoms of flexion spasms that lasted for a long period of time. These findings indicate that this is an effective and easy method of establishing a rat model of spastic cerebral palsy with good re-producibility. Ethanol as a chemical ablation agent specifically and thoroughly damages the pyramidal tract, and therefore, the animals display flexion spasms, which are a typical symptom of the disease. PMID:25206647

Intramuscular nerve distribution of the hamstring muscles: Application to treating spasticity.

PubMed

Rha, Dong-Wook; Yi, Kyu-Ho; Park, Eun Sook; Park, Chunung; Kim, Hee-Jin

2016-09-01

The aim of this article is to elucidate the ideal sites for botulinum toxin injection by examining the intramuscular nerve distributions in the hamstring muscles. The hamstring muscles, biceps femoris, semitendinosus, and semimembranosus (10 specimens each) were stained by the modified Sihler method. The locations of the muscle origins, nerve entry points, and intramuscular arborized areas were recorded as percentages of the total distance from the line crossing the medial and lateral tibial condyles (0%) to the ischial tuberosity (100%). Intramuscular arborization patterns were observed at 15-30% and 50-60% for the biceps femoris, 25-40% and 60-80% for the semitendinosus, and 20-40% for the semimembranosus. This study suggests that botulinum toxin injection for spasticity of the hamstring muscles should be targeted to specific areas. These areas, where the arborization of intramuscular nerve branches is maximal, are recommended as the most effective and safest points for injection. Clin. Anat. 29:746-751, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Directed intermittent search for a hidden target on a dendritic tree

NASA Astrophysics Data System (ADS)

Newby, Jay M.; Bressloff, Paul C.

2009-08-01

Motivated by experimental observations of active (motor-driven) intracellular transport in neuronal dendrites, we analyze a stochastic model of directed intermittent search on a tree network. A particle injected from the cell body or soma into the primary branch of the dendritic tree randomly switches between a stationary search phase and a mobile nonsearch phase that is biased in the forward direction. A (synaptic) target is presented somewhere within the tree, which the particle can locate if it is within a certain range and in the searching phase. We approximate the moment generating function using Green’s function methods. The moment generating function is then used to compute the hitting probability and conditional mean first passage time to the target. We show that in contrast to a previously explored finite interval case, there is a range of parameters for which a bidirectional search strategy is more efficient than a unidirectional one in finding the target.

DOTAM derivatives as active cartilage-targeting drug carriers for the treatment of osteoarthritis.

PubMed

Hu, Hai-Yu; Lim, Ngee-Han; Ding-Pfennigdorff, Danping; Saas, Joachim; Wendt, K Ulrich; Ritzeler, Olaf; Nagase, Hideaki; Plettenburg, Oliver; Schultz, Carsten; Nazare, Marc

2015-03-18

Targeted drug-delivery methods are crucial for effective treatment of degenerative joint diseases such as osteoarthritis (OA). Toward this goal, we developed a small multivalent structure as a model drug for the attenuation of cartilage degradation. The DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide)-based model structure is equipped with the cathepsin D protease inhibitor pepstatin A, a fluorophore, and peptide moieties targeting collagen II. In vivo injection of these soluble probes into the knee joints of mice resulted in 7-day-long local retention, while the drug carrier equipped with a scrambled peptide sequence was washed away within 6-8 h. The model drug conjugate successfully reduced the cathepsin D protease activity as measured by release of GAG peptide. Therefore, these conjugates represent a promising first drug conjugate for the targeted treatment of degenerative joint diseases.

Kepler Planet Detection Metrics: Per-Target Detection Contours for Data Release 25

NASA Technical Reports Server (NTRS)

Burke, Christopher J.; Catanzarite, Joseph

2017-01-01

A necessary input to planet occurrence calculations is an accurate model for the pipeline completeness (Burke et al., 2015). This document describes the use of the Kepler planet occurrence rate products in order to calculate a per-target detection contour for the measured Data Release 25 (DR25) pipeline performance. A per-target detection contour measures for a given combination of orbital period, Porb, and planet radius, Rp, what fraction of transit signals are recoverable by the Kepler pipeline (Twicken et al., 2016; Jenkins et al., 2017). The steps for calculating a detection contour follow the procedure outlined in Burke et al. (2015), but have been updated to provide improved accuracy enabled by the substantially larger database of transit injection and recovery tests that were performed on the final version (i.e., SOC 9.3) of the Kepler pipeline (Christiansen, 2017; Burke Catanzarite, 2017a). In the following sections, we describe the main inputs to the per-target detection contour and provide a worked example of the python software released with this document (Kepler Planet Occurrence Rate Tools KeplerPORTs)1 that illustrates the generation of a detection contour in practice. As background material for this document and its nomenclature, we recommend the reader be familiar with the previous method of calculating a detection contour (Section 2 of Burke et al.,2015), input parameters relevant for describing the data quantity and quality of Kepler targets (Burke Catanzarite, 2017b), and the extensive new transit injection and recovery tests of the Kepler pipeline (Christiansen et al., 2016; Burke Catanzarite, 2017a; Christiansen, 2017).

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

PubMed Central

D’Souza, Jimson W.; Hensley, Harvey; Doss, Mohan; Beigarten, Charles; Torgov, Michael; Olafsen, Tove; Yu, Jian Q.

2017-01-01

Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. Methods: The anti–prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. Results: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. Conclusion: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance. PMID:27539844

Preclinical Comparative Study of (68)Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA.

PubMed

Ray Banerjee, Sangeeta; Chen, Zhengping; Pullambhatla, Mrudula; Lisok, Ala; Chen, Jian; Mease, Ronnie C; Pomper, Martin G

2016-06-15

(68)Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: (68)Ga-1, using DOTA-monoamide as the chelating agent; (68)Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and (68)Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). (68)Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to (68)Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. (68)Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation (68)Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging.

Numerical investigation of liver radioembolization via computational particle-hemodynamics: The role of the microcatheter distal direction and microsphere injection point and velocity.

PubMed

Aramburu, Jorge; Antón, Raúl; Rivas, Alejandro; Ramos, Juan Carlos; Sangro, Bruno; Bilbao, José Ignacio

2016-11-07

Liver radioembolization is a treatment option for patients with primary and secondary liver cancer. The procedure consists of injecting radiation-emitting microspheres via an intra-arterially placed microcatheter, enabling the deposition of the microspheres in the tumoral bed. The microcatheter location and the particle injection rate are determined during a pretreatment work-up. The purpose of this study was to numerically study the effects of the injection characteristics during the first stage of microsphere travel through the bloodstream in a patient-specific hepatic artery (i.e., the near-tip particle-hemodynamics and the segment-to-segment particle distribution). Specifically, the influence of the distal direction of an end-hole microcatheter and particle injection point and velocity were analyzed. Results showed that the procedure targeted the right lobe when injecting from two of the three injection points under study and the remaining injection point primarily targeted the left lobe. Changes in microcatheter direction and injection velocity resulted in an absolute difference in exiting particle percentage for a given liver segment of up to 20% and 30%, respectively. It can be concluded that even though microcatheter placement is presumably reproduced in the treatment session relative to the pretreatment angiography, the treatment may result in undesired segment-to-segment particle distribution and therefore undesired treatment outcomes due to modifications of any of the parameters studied, i.e., microcatheter direction and particle injection point and velocity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oncolytic Adenoviruses Targeted to Human Papilloma Virus-Positive Head and Neck Squamous Cell Carcinomas

PubMed Central

LaRocca, Christopher J.; Han, Joohee; Oliveira, Amanda R.; Davydova, Julia; Herzberg, Mark; Gopalakrishnan, Rajaram; Yamamoto, Masato

2016-01-01

Objectives In recent years, the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has markedly increased. Our aim was to design a novel therapeutic agent through the use of conditionally replicative adenoviruses (CRAds) that are targeted to the HPV E6 and E7 oncoproteins. Methods Each adenovirus included small deletion(s) in the E1a region of the genome (Δ24 or CB016) intended to allow for selective replication in HPV-positive cells. In vitro assays were performed to analyze the transduction efficiency of the vectors and the cell viability following viral infection. Then, the UPCI SCC 090 cell line (HPV-positive) was used to establish subcutaneous tumors in the flanks of nude mice. The tumors were then treated with either one dose of the virus or four doses (injected every fourth day). Results The transduction analysis with luciferase-expressing viruses demonstrated that the 5/3 fiber modification maximized virus infectivity. In vitro, both viruses (5/3Δ24 and 5/3CB016) demonstrated profound oncolytic effects. The 5/3CB016 virus was selective for only HPV-positive HNSCC cells, whereas the 5/3Δ24 virus killed HNSCC cells regardless of HPV status. In vivo, single injections of both viruses demonstrated anti-tumor effects until only 6–8 days following viral inoculation. However, after four viral injections, there was statistically significant reduction in tumor growth when compared to the control group (p<0.05). Conclusion CRAds targeted to HPV-positive HNSCCs demonstrated excellent in vitro and in vivo therapeutic effects, and they have the potential to be clinically translated as a novel treatment modality for this emerging disease. PMID:27086483

Targeted mutagenesis in sea urchin embryos using TALENs.

PubMed

Hosoi, Sayaka; Sakuma, Tetsushi; Sakamoto, Naoaki; Yamamoto, Takashi

2014-01-01

Genome editing with engineered nucleases such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) has been reported in various animals. We previously described ZFN-mediated targeted mutagenesis and insertion of reporter genes in sea urchin embryos. In this study, we demonstrate that TALENs can induce mutagenesis at specific genomic loci of sea urchin embryos. Injection of TALEN mRNAs targeting the HpEts transcription factor into fertilized eggs resulted in the impairment of skeletogenesis. Sequence analyses of the mutations showed that deletions and/or insertions occurred at the HpEts target site in the TALEN mRNAs-injected embryos. The results suggest that targeted gene disruption using TALENs is feasible in sea urchin embryos. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

Dynamic leaching and fractionation of trace elements from environmental solids exploiting a novel circulating-flow platform.

PubMed

Mori, Masanobu; Nakano, Koji; Sasaki, Masaya; Shinozaki, Haruka; Suzuki, Shiho; Okawara, Chitose; Miró, Manuel; Itabashi, Hideyuki

2016-02-01

A dynamic flow-through microcolumn extraction system based on extractant re-circulation is herein proposed as a novel analytical approach for simplification of bioaccessibility tests of trace elements in sediments. On-line metal leaching is undertaken in the format of all injection (AI) analysis, which is a sequel of flow injection analysis, but involving extraction under steady-state conditions. The minimum circulation times and flow rates required to determine the maximum bioaccessible pools of target metals (viz., Cu, Zn, Cd, and Pb) from lake and river sediment samples were estimated using Tessier's sequential extraction scheme and an acid single extraction test. The on-line AIA method was successfully validated by mass balance studies of CRM and real sediment samples. Tessier's test in on-line AI format demonstrated to be carried out by one third of extraction time (6h against more than 17 h by the conventional method), with better analytical precision (<9.2% against >15% by the conventional method) and significant decrease in blank readouts as compared with the manual batch counterpart. Copyright © 2015 Elsevier B.V. All rights reserved.

A morphological evaluation of botulinum neurotoxin A injections into the detrusor muscle using magnetic resonance imaging.

PubMed

Mehnert, Ulrich; Boy, Sönke; Schmid, Marius; Reitz, André; von Hessling, Alexander; Hodler, Juerg; Schurch, Brigitte

2009-06-01

Although botulinum neurotoxin type A (BoNT/A) intradetrusor injections are a recommended therapy for neurogenic detrusor overactivity (NDO), refractory to antimuscarinic drugs, a standardisation of injection technique is missing. Furthermore, some basic questions are still unanswered, as where the toxin solution exactly spreads after injection. Therefore, we investigated the distribution of the toxin solution after injection into the bladder wall, using magnet resonance imaging (MRI). Six patients with NDO were recruited. Three of six patients received 300 U of BoNT/A + contrast agent distributed over 30 injection sites (group 1). The other three patients received 300 U of BoNT/A + contrast agent distributed over 10 injection sites (group 2). Immediately after injection, MRI of the pelvis was performed. The volume of the detrusor and the total volume of contrast medium inside and outside the bladder wall were calculated. In all patients, a small volume (mean 17.6%) was found at the lateral aspects of the bladder dome in the extraperitoneal fat tissue, whereas 82.4% of the injected volume reached the target area (detrusor). In both groups there was a similar distribution of the contrast medium in the target area. A mean of 33.3 and 25.3% of the total detrusor volume was covered in group 1 and 2, respectively. Six weeks after injection, five of six patients were continent and showed no detrusor overactivity in the urodynamic follow-up. No systemic side effects were observed. Our results provide morphological arguments that the currently used injection techniques are appropriate and safe.

Optimization of the production of knock-in alleles by CRISPR/Cas9 microinjection into the mouse zygote.

PubMed

Raveux, Aurélien; Vandormael-Pournin, Sandrine; Cohen-Tannoudji, Michel

2017-02-17

Microinjection of the CRISPR/Cas9 system in zygotes is an efficient and comparatively fast method to generate genetically modified mice. So far, only few knock-in mice have been generated using this approach, and because no systematic study has been performed, parameters controlling the efficacy of CRISPR/Cas9-mediated targeted insertion are not fully established. Here, we evaluated the effect of several parameters on knock-in efficiency changing only one variable at a time. We found that knock-in efficiency was dependent on injected Cas9 mRNA and single-guide RNA concentrations and that cytoplasmic injection resulted in more genotypic complexity compared to pronuclear injection. Our results also indicated that injection into the pronucleus compared to the cytoplasm is preferable to generate knock-in alleles with an oligonucleotide or a circular plasmid. Finally, we showed that Cas9D10A nickase variant was less efficient than wild-type Cas9 for generating knock-in alleles and caused a higher rate of mosaicism. Thus, our study provides valuable information that will help to improve the future production of precise genetic modifications in mice.

Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.

PubMed

Sugano, M; Makino, N; Sawada, S; Otsuka, S; Watanabe, M; Okamoto, H; Kamada, M; Mizushima, A

1998-02-27

Cholesteryl ester transfer protein (CETP) is the enzyme that facilitates the transfer of cholesteryl ester from high density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoproteins. However, the exact role of CETP in the development of atherosclerosis has not been determined. In the present study, we examined the effect of the suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the development of atherosclerosis in rabbits fed a cholesterol diet. The ODNs against rabbit CETP were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method to regulate liver gene expression. Twenty-two male Japanese White rabbits were used in the experiment. Eighteen animals were fed a standard rabbit chow supplemented with 0.3% cholesterol throughout the experiment for 16 weeks. At 8 weeks, they were divided into three groups (six animals in each group), among which the plasma total and HDL cholesterol concentrations did not significantly change. The control group received nothing, the sense group were injected with the sense ODNs complex, and the antisense group were injected with the antisense ODNs complex, respectively, for subsequent 8 weeks. ASOR. poly(L-lysine) ODNs complex were injected via the ear veins twice a week. Four animals were fed a standard rabbit diet for 16 weeks. The total cholesterol concentrations and the CETP mass in the animals injected with antisense ODNs were all significantly decreased in 12 and 16 weeks compared with those injected with sense ODNs and the control animals. The HDL cholesterol concentrations measured by the precipitation assay did not significantly change among the groups fed a cholesterol diet, and triglyceride concentrations did not significantly change in the four groups. However, at the end of the study, when the HDL cholesterol concentrations were measured after the isolation by ultracentrifugation and a column chromotography, they were significantly higher in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. A reduction of CETP mRNA and an increase of LDL receptor mRNA in the liver were observed in the animals injected with antisense ODNs compared with those injected with sense ODNs and the control animals. Aortic cholesterol contents and the aortic percentage lesion to total surface area were significantly lower in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. These findings showed for the first time that suppression of increased plasma CETP by the injection with antisense ODNs against CETP coupled to ASOR carrier molecules targeted to the liver could thus inhibit the atherosclerosis possibly by decreasing the plasma LDL + very low density lipoprotein (VLDL) cholesterol in cholesterol-fed rabbits.

Evaluating the Gutenberg-Richter Relationship for Induced Seismicity

NASA Astrophysics Data System (ADS)

Tymchak, M. P.; Flewelling, S. A.

2013-12-01

Large volumes of flowback and produced water generated from hydraulic fracturing and oil and gas production have led to increased wastewater disposal through underground injection wells. Several recent studies have linked recently felt seismic events to underground injection wells in Arkansas, Ohio, Texas and Oklahoma, among others. However, in some cases, such as in Oklahoma, there is a lack of consensus as to whether the earthquakes were the result of fluid injection (Keranan et al., 2013), natural tectonic processes (Oklahoma Geological Survey, 2013), or were related to remote events (van der Elst et al., 2013). Moreover, it is unclear why earthquakes have occurred near some injection wells but not others, with apparently similar geology, target reservoirs, and injection rates (e.g., Frohlich, 2012). In instances where injection occurred near a fault (e.g., Rangely, CO), the timing and distribution of seismic events was well correlated to fluid volumes, and the interaction between injection and induced seismicity was easily resolved. In other cases (e.g., Oklahoma, Texas), it appears more difficult to interpret whether a particular injection well was related to observed seismic events. Therefore, metrics are needed as diagnostic tools to help differentiate between natural and induced seismicity. It has been well established that the frequency-magnitude distribution of earthquakes follows the Gutenberg-Richter distribution log N(M) = a - bM, where the slope (b-value) is typically near one. However, in some instances of deep fluid injection, b-values may vary, depending on specific injection activities, such as enhanced geothermal or hydraulic fracturing (Dinske and Shapiro, 2013). In some cases, b-values may vary during successive fracture stages of a single horizontal well (e.g., Williams and Calvarez, 2013), and seismicity associated with hydraulic fracturing may deviate from the Gutenberg-Richter relationship altogether (Hurd and Zoback, 2012). We evaluate whether frequency magnitude distributions could be used as a method to distinguish between natural and induced seismicity, drawing from a number of datasets compiled from different types of injection activities.

Plasmonic nanobubbles for target cell-specific gene and drug delivery and multifunctional processing of heterogeneous cell systems

NASA Astrophysics Data System (ADS)

Lukianova-Hleb, Ekaterina Y.; Huye, Leslie E.; Brenner, Malcolm K.; Lapotko, Dmitri O.

2014-03-01

Cell and gene cancer therapies require ex vivo cell processing of human grafts. Such processing requires at least three steps - cell enrichment, cell separation (destruction), and gene transfer - each of which requires the use of a separate technology. While these technologies may be satisfactory for research use, they are of limited usefulness in the clinical treatment setting because they have a low processing rate, as well as a low transfection and separation efficacy and specificity in heterogeneous human grafts. Most problematic, because current technologies are administered in multiple steps - rather than in a single, multifunctional, and simultaneous procedure - they lengthen treatment process and introduce an unnecessary level of complexity, labor, and resources into clinical treatment; all these limitations result in high losses of valuable cells. We report a universal, high-throughput, and multifunctional technology that simultaneously (1) inject free external cargo in target cells, (2) destroys unwanted cells, and (3) preserve valuable non-target cells in heterogeneous grafts. Each of these functions has single target cell specificity in heterogeneous cell system, processing rate > 45 mln cell/min, injection efficacy 90% under 96% viability of the injected cells, target cell destruction efficacy > 99%, viability of not-target cells >99% The developed technology employs novel cellular agents, called plasmonic nanobubbles (PNBs). PNBs are not particles, but transient, intracellular events, a vapor nanobubbles that expand and collapse in mere nanoseconds under optical excitation of gold nanoparticles with short picosecond laser pulses. PNBs of different, cell-specific, size (1) inject free external cargo with small PNBs, (2) Destroy other target cells mechanically with large PNBs and (3) Preserve non-target cells. The multi-functionality, precision, and high throughput of all-in-one PNB technology will tremendously impact cell and gene therapies and other clinical applications that depend on ex vivo processing of heterogeneous cell systems.

The Potosi Reservoir Model 2013c, Property Modeling Update

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adushita, Yasmin; Smith, Valerie; Leetaru, Hannes

2014-09-30

As part of a larger project co-funded by the United States Department of Energy (US DOE) to evaluate the potential of formations within the Cambro-Ordovician strata above the Mt. Simon as potential targets for carbon sequestration in the Illinois and Michigan Basins, the Illinois Clean Coal Institute (ICCI) requested Schlumberger to evaluate the potential injectivity and carbon dioxide (CO2) plume size of the Cambrian Potosi Formation. The evaluation of this formation was accomplished using wireline data, core data, pressure data, and seismic data from this project as well as two other separately funded projects: the US DOE-funded Illinois Basin–Decatur Projectmore » (IBDP) being conducted by the Midwest Geological Sequestration Consortium (MGSC) in Macon County, Illinois, and the Illinois Industrial Carbon Capture and Sequestration (ICCS) project funded through the American Recovery and Reinvestment Act. In 2010, technical performance evaluations on the Cambrian Potosi Formation were performed through reservoir modeling. The data included formation tops from mud logs, well logs from the Verification Well #1 (VW1) and the Injection Well (CCS1), structural and stratigraphic formation from three dimensional (3D) seismic data, and field data from several waste water injection wells for Potosi Formation. The intention was for 2.2 million tons per annum (2 million tonnes per annum [MTPA]) of CO2 to be injected for 20 years. In the Task Error! Reference source not found., the 2010 Potosi heterogeneous model (referred to as the "Potosi Dynamic Model 2010") was re-run using a new injection scenario of 3.5 million tons per annum (3.2 MTPA) for 30 years. The extent of the Potosi Dynamic Model 2010, however, appeared too small for the new injection target. The models size was insufficient to accommodate the evolution of the plume. The new model, Potosi Dynamic Model 2013a, was built by extending the Potosi Dynamic Model 2010 grid to 30 by 30 mi (48 by 48 km), while preserving all property modeling workflows and layering. This model was retained as the base case. In the preceding Task [1], the Potosi reservoir model was updated to take into account the new data from the Verification Well #2 (VW2) which was drilled in 2012. The porosity and permeability modeling was revised to take into account the log data from the new well. Revisions of the 2010 modeling assumptions were also done on relative permeability, capillary pressures, formation water salinity, and the maximum allowable well bottomhole pressure. Dynamic simulations were run using the injection target of 3.5 million tons per annum (3.2 MTPA) for 30 years. This dynamic model was named Potosi Dynamic Model 2013b. In this Task, a new property modeling workflow was applied, where seismic inversion data guided the porosity mapping and geobody extraction. The static reservoir model was fully guided by PorosityCube interpretations and derivations coupled with petrophysical logs from three wells. The two main assumptions are: porosity features in the PorosityCube that correlate with lost circulation zones represent vugular zones, and that these vugular zones are laterally continuous. Extrapolation was done carefully to populate the vugular facies and their corresponding properties outside the seismic footprint up to the boundary of the 30 by 30 mi (48 by 48 km) model. Dynamic simulations were also run using the injection target of 3.5 million tons per annum (3.2 MTPA) for 30 years. This new dynamic model was named Potosi Dynamic Model 2013c. Reservoir simulation with the latest model gives a cumulative injection of 43 million tons (39 MT) in 30 years with a single well, which corresponds to 40% of the injection target. The injection rate is approx. 3.2 MTPA in the first six months as the well is injecting into the surrounding vugs, and declines rapidly to 1.8 million tons per annum (1.6 MTPA) in year 3 once the surrounding vugs are full and the CO2 start to reach the matrix. After, the injection rate declines gradually to 1.2 million tons per annum (1.1 MTPA) in year 18 and stays constant. This implies that a minimum of three (3) wells could be required in the Potosi to reach the injection target. The injectivity evaluated in this Task was higher compared to the preceding Task, since the current facies modeling (guided by the porosity map from the seismic inversion) indicated a higher density of vugs within the vugular zones. 5 As the CO2 follows the paths where vugs interconnection exists, a reasonably large and irregular plume extent was created. After 30 years of injection, the plume extends 13.7 mi (22 km) in E-W and 9.7 mi (16 km) in N-S directions. After injection finishes, the plume continues to migrate laterally, mainly driven by the remaining pressure gradient. After 60 years post-injection, the plume extends 14.2 mi (22.8 km) in E-W and 10 mi (16 km) in N-S directions, and remains constant as the remaining pressure gradient has become very low. Should the targeted cumulative injection of 106 million tons (96 MT) be achieved; a much larger plume extent could be expected. The increase of reservoir pressure at the end of injection is approximately 1,200 psia (8,274 kPa) around the injector and gradually decreases away from the well. The reservoir pressure increase is less than 10 psia (69 kPa) beyond 14 mi (23 km) away from injector. Should the targeted cumulative injection of 106 million tons (96 MT) be achieved; a much larger areal pressure increase could be expected. The reservoir pressure declines rapidly during the first 30 years post injection and the initial reservoir pressure is nearly restored after 100 years post-injection. The present evaluation is mainly associated with uncertainty on the vugs permeability and interconnectivity. The use of porosity mapping from seismic inversion might have reduced the uncertainty on the lateral vugs body distributions. However, major uncertainties on the Potosi vugs permeability remains. Therefore, injection test and pressure interference test among the wells could be considered to evaluate the local vugs permeability, extent, and interconnectivity. Facies modeling within the Potosi has yet to be thoroughly addressed. The carbonates during the time of deposition are believed to be regionally extensive. However, it may be worth delineating the reservoir with other regional wells or modern day analogues to understand the extent of the Potosi. More specifically, the model could incorporate lateral changes or trends if deemed necessary to represent facies transition. Data acquisitions to characterize the fracture pressure gradient, the formation water properties, the relative permeability, and the capillary pressure could also be considered in order to allow a more rigorous evaluation of the Potosi storage performance. A simulation using several injectors could also be considered to determine the required number of wells and appropriate spacing to achieve the injection target while taking into account the pressure interference.« less

Quantitative Comparison of Tumor Delivery for Multiple Targeted Nanoparticles Simultaneously by Multiplex ICP-MS

PubMed Central

Elias, Andrew; Crayton, Samuel H.; Warden-Rothman, Robert; Tsourkas, Andrew

2014-01-01

Given the rapidly expanding library of disease biomarkers and targeting agents, the number of unique targeted nanoparticles is growing exponentially. The high variability and expense of animal testing often makes it unfeasible to examine this large number of nanoparticles in vivo. This often leads to the investigation of a single formulation that performed best in vitro. However, nanoparticle performance in vivo depends on many variables, many of which cannot be adequately assessed with cell-based assays. To address this issue, we developed a lanthanide-doped nanoparticle method that allows quantitative comparison of multiple targeted nanoparticles simultaneously. Specifically, superparamagnetic iron oxide (SPIO) nanoparticles with different targeting ligands were created, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood and resected tumor samples. PMID:25068300

Opto-injection into single living cells by femtosecond near-infrared laser

NASA Astrophysics Data System (ADS)

Peng, Cheng

This dissertation presents a novel technique to deliver membrane impermeable molecules into single living cells with the assistance of femtosecond (fs) near-infrared (NIR) laser pulses. This approach merges ultrafast laser technology with key biological, biomedical, and medical applications, such as gene transfection, gene therapy and drug delivery. This technique promises several major advantages, namely, very high transfection efficiency, high cell survival rate (≈100%) and fully preserved cell viabilities. It is also a promising method to deliver molecules into cells that are difficult or even completely resistant to established physical methods, such as microinjection by glass pipettes, electroporation, and biolistics. In this work, the system for fs NIR opto-injection was designed and built. Successful fs NIR opto-injection has been performed on several cell systems including single mammalian cells (bovine aortic endothelial cells), marine animal eggs (Spisula solidissima oocytes), and human cancer cells (fibrosarcoma HT1080) cultured in a tissue-like environment. The connections between laser parameters and cell responses were explored through further experiments and in-depth analyses, especially the relationship between dye uptake rate and incident laser intensity, and the relationship between pore size created on cell membranes and incident laser intensity. Dye uptake rate of the target cells was observed to depend on incident laser intensity. Pore size was found dependent on incident laser intensity. The conclusion was made that laser-induced breakdown and plasma-induced ablation in cell membrane are the physical principles that govern the process of fs NIR opto-injection.

Syringe Injectable Electronics: Precise Targeted Delivery with Quantitative Input/Output Connectivity.

PubMed

Hong, Guosong; Fu, Tian-Ming; Zhou, Tao; Schuhmann, Thomas G; Huang, Jinlin; Lieber, Charles M

2015-10-14

Syringe-injectable mesh electronics with tissue-like mechanical properties and open macroporous structures is an emerging powerful paradigm for mapping and modulating brain activity. Indeed, the ultraflexible macroporous structure has exhibited unprecedented minimal/noninvasiveness and the promotion of attractive interactions with neurons in chronic studies. These same structural features also pose new challenges and opportunities for precise targeted delivery in specific brain regions and quantitative input/output (I/O) connectivity needed for reliable electrical measurements. Here, we describe new results that address in a flexible manner both of these points. First, we have developed a controlled injection approach that maintains the extended mesh structure during the "blind" injection process, while also achieving targeted delivery with ca. 20 μm spatial precision. Optical and microcomputed tomography results from injections into tissue-like hydrogel, ex vivo brain tissue, and in vivo brains validate our basic approach and demonstrate its generality. Second, we present a general strategy to achieve up to 100% multichannel I/O connectivity using an automated conductive ink printing methodology to connect the mesh electronics and a flexible flat cable, which serves as the standard "plug-in" interface to measurement electronics. Studies of resistance versus printed line width were used to identify optimal conditions, and moreover, frequency-dependent noise measurements show that the flexible printing process yields values comparable to commercial flip-chip bonding technology. Our results address two key challenges faced by syringe-injectable electronics and thereby pave the way for facile in vivo applications of injectable mesh electronics as a general and powerful tool for long-term mapping and modulation of brain activity in fundamental neuroscience through therapeutic biomedical studies.

EMMPRIN-Targeted Magnetic Nanoparticles for In Vivo Visualization and Regression of Acute Myocardial Infarction.

PubMed

Cuadrado, Irene; Piedras, Maria Jose Garcia Miguel; Herruzo, Irene; Turpin, Maria Del Carmen; Castejón, Borja; Reventun, Paula; Martin, Ana; Saura, Marta; Zamorano, Jose Luis; Zaragoza, Carlos

2016-01-01

Inhibition of extracellular matrix (ECM) degradation may represent a mechanism for cardiac protection against ischemia. Extracellular matrix metalloproteinase inducer (EMMPRIN) is highly expressed in response to acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including gelatinases MMP-2 and MMP-9. We targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles conjugated with the EMMPRIN binding peptide AP-9 (NAP9), or an AP-9 scrambled peptide as a negative control (NAPSC). We found that NAP9 binds to endogenous EMMPRIN in cultured HL1 myocytes and in mouse hearts subjected to ischemia/reperfusion (IR). Injection of NAP9 at the time of or one day after IR, was enough to reduce progression of myocardial cell death when compared to CONTROL and NAPSC injected mice (infarct size in NAP9 injected mice: 32%±6.59 vs 46%±9.04 or NAPSC injected mice: 48%±7.64). In the same way, cardiac parameters were recovered to almost healthy levels (LVEF NAP9 63% ± 7.24 vs CONTROL 42% ± 4.74 or NAPSC 39% ± 6.44), whereas ECM degradation was also reduced as shown by inhibition of MMP-2 and MMP-9 activation. Cardiac magnetic resonance (CMR) scans have shown a signal enhancement in the left ventricle of NAP9 injected mice with respect to non-injected, and to mice injected with NAPSC. A positive correlation between CMR enhancement and Evans-Blue/TTC staining of infarct size was calculated (R:0.65). Taken together, these results point to EMMPRIN targeted nanoparticles as a new approach to the mitigation of ischemic/reperfusion injury.

Field demonstration of DNAPL dehalogenation using emulsified zero-valent iron

NASA Technical Reports Server (NTRS)

Quinn, Jacqueline; Geiger, Cherie; Clausen, Chris; Brooks, Kathleen; Coon, Christina; O'Hara, Suzanne; Krug, Thomas; Major, David; Yoon, Woong-Sang; Gavaskar, Arun;

Field Demonstration of DNAPL Dehalogenation Using Emulsified Zero-Valent Iron

NASA Technical Reports Server (NTRS)

Quinn, Jacqueline; Geiger, Cherie; Clausen, Chris; Brooks, Kathleen; Coon, Christina; O'Hara, Suzanne; Krug, Thomas; Major, David; Yoon, Sam; Gavaskar, Arun;

Estimating the number of injecting drug users in Scotland's HCV-diagnosed population using capture-recapture methods.

PubMed

McDonald, S A; Hutchinson, S J; Schnier, C; McLeod, A; Goldberg, D J

2014-01-01

In countries maintaining national hepatitis C virus (HCV) surveillance systems, a substantial proportion of individuals report no risk factors for infection. Our goal was to estimate the proportion of diagnosed HCV antibody-positive persons in Scotland (1991-2010) who probably acquired infection through injecting drug use (IDU), by combining data on IDU risk from four linked data sources using log-linear capture-recapture methods. Of 25,521 HCV-diagnosed individuals, 14,836 (58%) reported IDU risk with their HCV diagnosis. Log-linear modelling estimated a further 2484 HCV-diagnosed individuals with IDU risk, giving an estimated prevalence of 83. Stratified analyses indicated variation across birth cohort, with estimated prevalence as low as 49% in persons born before 1960 and greater than 90% for those born since 1960. These findings provide public-health professionals with a more complete profile of Scotland's HCV-infected population in terms of transmission route, which is essential for targeting educational, prevention and treatment interventions.

DryLab® optimised two-dimensional high performance liquid chromatography for differentiation of ephedrine and pseudoephedrine based methamphetamine samples.

PubMed

Andrighetto, Luke M; Stevenson, Paul G; Pearson, James R; Henderson, Luke C; Conlan, Xavier A

2014-11-01

In-silico optimised two-dimensional high performance liquid chromatographic (2D-HPLC) separations of a model methamphetamine seizure sample are described, where an excellent match between simulated and real separations was observed. Targeted separation of model compounds was completed with significantly reduced method development time. This separation was completed in the heart-cutting mode of 2D-HPLC where C18 columns were used in both dimensions taking advantage of the selectivity difference of methanol and acetonitrile as the mobile phases. This method development protocol is most significant when optimising the separation of chemically similar chemical compounds as it eliminates potentially hours of trial and error injections to identify the optimised experimental conditions. After only four screening injections the gradient profile for both 2D-HPLC dimensions could be optimised via simulations, ensuring the baseline resolution of diastereomers (ephedrine and pseudoephedrine) in 9.7 min. Depending on which diastereomer is present the potential synthetic pathway can be categorized.

Efficacy of Intravitreal injection of 2-Methoxyestradiol in regression of neovascularization of a retinopathy of prematurity rat model.

PubMed

Said, Azza Mohamed Ahmed; Zaki, Rania Gamal Eldin; Salah Eldin, Rania A; Nasr, Maha; Azab, Samar Saad; Elzankalony, Yaser Abdelmageuid

2017-04-04

Retinopathy of prematurity (ROP) is one of the targets for early detection and treatment to prevent childhood blindness in world health organization programs. The purpose of study was to evaluate the efficacy of intravitreal injection of 2-Methoxyestradiol (2-ME) nanoemulsion in regressing neovascularization of a ROP rat model. A prospective comparative case - control animal study conducted on 56 eyes of 28 healthy new born Sprague Dawley male albino rat. ROP was induced in 21 rats then two concentrations of 2-ME nanoparticles were injected in right eyes of 14 rats (low dose; study group I, high dose; study group II). A blank nanoemulsion was injected in the right eyes of seven rats (control positive group I). No injections performed in contralateral left eyes (control positive group II). Seven rats (14 eyes) were kept in room air (control negative group). On postnatal day 17, eyeballs were enucleated. Histological structure of the retina was examined using Hematoxylin and eosin staining. Vascular endothelial growth factor (VEGF) and glial fibrillary acidic protein (GFAP) expressions were detected by immunohistochemical studies. Intravitreal injection of 2-ME (in the two concentrations) caused marked regression of the new vascular tufts on the vitreal side with normal organization and thickness of the retina especially in study group II, which also show negative VEGF immunoreaction. Positive GFAP expression was detected in the control positive groups and study group (I). Intravitreal injection of 2-Methoxyestradiol nanoemulsion is a promising effective method in reduction of neovascularization of a ROP rat model.

High resolution 3D MRI of mouse mammary glands with intra-ductal injection of contrast media.

PubMed

Markiewicz, Erica; Fan, Xiaobing; Mustafi, Devkumar; Zamora, Marta; Roman, Brian B; Jansen, Sanaz A; Macleod, Kay; Conzen, Suzanne D; Karczmar, Gregory S

2015-01-01

The purpose of this study was to use high resolution three-dimensional (3D) magnetic resonance imaging (MRI) to study mouse mammary gland ductal architecture based on intra-ductal injection of contrast agents. Female FVB/N mice age 12-20 weeks (n=12), were used in this study. A 34G, 45° tip Hamilton needle with a 25μL Hamilton syringe was inserted into the tip of the nipple. Approximately 20-25μL of a Gadodiamide/Trypan blue/saline solution was injected slowly over one minute into the nipple and duct. To prevent washout of contrast media from ducts due to perfusion, and maximize the conspicuity of ducts on MRI, mice were sacrificed one minute after injection. High resolution 3D T1-weighted images were acquired on a 9.4T Bruker scanner after sacrifice to eliminate motion artifacts and reduce contrast media leakage from ducts. Trypan blue staining was well distributed throughout the ductal tree. MRI showed the mammary gland ductal structure clearly. In spoiled gradient echo T1-weighted images, the signal-to-noise ratio of regions identified as enhancing mammary ducts following contrast injection was significantly higher than that of muscle (p<0.02) and significantly higher than that of contralateral mammary ducts that were not injected with contrast media (p<0.0001). The methods described here could be adapted for injection of specialized contrast agents to measure metabolism or target receptors in normal ducts and ducts with in situ cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

Item Anomaly Detection Based on Dynamic Partition for Time Series in Recommender Systems

PubMed Central

Gao, Min; Tian, Renli; Wen, Junhao; Xiong, Qingyu; Ling, Bin; Yang, Linda

2015-01-01

In recent years, recommender systems have become an effective method to process information overload. However, recommendation technology still suffers from many problems. One of the problems is shilling attacks-attackers inject spam user profiles to disturb the list of recommendation items. There are two characteristics of all types of shilling attacks: 1) Item abnormality: The rating of target items is always maximum or minimum; and 2) Attack promptness: It takes only a very short period time to inject attack profiles. Some papers have proposed item anomaly detection methods based on these two characteristics, but their detection rate, false alarm rate, and universality need to be further improved. To solve these problems, this paper proposes an item anomaly detection method based on dynamic partitioning for time series. This method first dynamically partitions item-rating time series based on important points. Then, we use chi square distribution (χ2) to detect abnormal intervals. The experimental results on MovieLens 100K and 1M indicate that this approach has a high detection rate and a low false alarm rate and is stable toward different attack models and filler sizes. PMID:26267477

Item Anomaly Detection Based on Dynamic Partition for Time Series in Recommender Systems.

PubMed

Gao, Min; Tian, Renli; Wen, Junhao; Xiong, Qingyu; Ling, Bin; Yang, Linda

2015-01-01

In recent years, recommender systems have become an effective method to process information overload. However, recommendation technology still suffers from many problems. One of the problems is shilling attacks-attackers inject spam user profiles to disturb the list of recommendation items. There are two characteristics of all types of shilling attacks: 1) Item abnormality: The rating of target items is always maximum or minimum; and 2) Attack promptness: It takes only a very short period time to inject attack profiles. Some papers have proposed item anomaly detection methods based on these two characteristics, but their detection rate, false alarm rate, and universality need to be further improved. To solve these problems, this paper proposes an item anomaly detection method based on dynamic partitioning for time series. This method first dynamically partitions item-rating time series based on important points. Then, we use chi square distribution (χ2) to detect abnormal intervals. The experimental results on MovieLens 100K and 1M indicate that this approach has a high detection rate and a low false alarm rate and is stable toward different attack models and filler sizes.

Iodine speciation in coastal and inland bathing waters and seaweeds extracts using a sequential injection standard addition flow-batch method.

PubMed

Santos, Inês C; Mesquita, Raquel B R; Bordalo, Adriano A; Rangel, António O S S

2015-02-01

The present work describes the development of a sequential injection standard addition method for iodine speciation in bathing waters and seaweeds extracts without prior sample treatment. Iodine speciation was obtained by assessing the iodide and iodate content, the two inorganic forms of iodine in waters. For the determination of iodide, an iodide ion selective electrode (ISE) was used. The indirect determination of iodate was based on the spectrophotometric determination of nitrite (Griess reaction). For the iodate measurement, a mixing chamber was employed (flow batch approach) to explore the inherent efficient mixing, essential for the indirect determination of iodate. The application of the standard addition method enabled detection limits of 0.14 µM for iodide and 0.02 µM for iodate, together with the direct introduction of the target water samples, coastal and inland bathing waters. The results obtained were in agreement with those obtained by ICP-MS and a colorimetric reference procedure. Recovery tests also confirmed the accuracy of the developed method which was effectively applied to bathing waters and seaweed extracts. Copyright © 2014 Elsevier B.V. All rights reserved.

Development and characterization of plasma targets for controlled injection of electrons into laser-driven wakefields

NASA Astrophysics Data System (ADS)

Kleinwaechter, Tobias; Goldberg, Lars; Palmer, Charlotte; Schaper, Lucas; Schwinkendorf, Jan-Patrick; Osterhoff, Jens

2012-10-01

Laser-driven wakefield acceleration within capillary discharge waveguides has been used to generate high-quality electron bunches with GeV-scale energies. However, owing to fluctuations in laser and plasma conditions in combination with a difficult to control self-injection mechanism in the non-linear wakefield regime these bunches are often not reproducible and can feature large energy spreads. Specialized plasma targets with tailored density profiles offer the possibility to overcome these issues by controlling the injection and acceleration processes. This requires precise manipulation of the longitudinal density profile. Therefore our target concept is based on a capillary structure with multiple gas in- and outlets. Potential target designs are simulated using the fluid code OpenFOAM and those meeting the specified criteria are fabricated using femtosecond-laser machining of structures into sapphire plates. Density profiles are measured over a range of inlet pressures utilizing gas-density profilometry via Raman scattering and pressure calibration with longitudinal interferometry. In combination these allow absolute density mapping. Here we report the preliminary results.

Rapid Decline in HIV Incidence Among Persons Who Inject Drugs During a Fast-Track Combination Prevention Program After an HIV Outbreak in Athens

PubMed Central

Psichogiou, Mina; Paraskevis, Dimitrios; Nikolopoulos, Georgios; Tsiara, Chrissa; Paraskeva, Dimitra; Micha, Katerina; Malliori, Meni; Pharris, Anastasia; Wiessing, Lucas; Donoghoe, Martin; Friedman, Samuel; Jarlais, Don Des; Daikos, Georgios; Hatzakis, Angelos

2017-01-01

Abstract Background. A “seek-test-treat” intervention (ARISTOTLE) was implemented in response to an outbreak of human immunodeficiency virus (HIV) infection among persons who inject drugs (PWID) in Athens. We assess trends in HIV incidence, prevalence, risk behaviors and access to prevention/treatment. Methods. Methods included behavioral data collection, provision of injection equipment, HIV testing, linkage to opioid substitution treatment (OST) programs and HIV care during 5 rounds of respondent-driven sampling (2012–2013). HIV incidence was estimated from observed seroconversions. Results. Estimated coverage of the target population was 88% (71%–100%; 7113 questionnaires/blood samples from 3320 PWID). The prevalence of HIV infection was 16.5%. The incidence per 100 person-years decreased from 7.8 (95% confidence interval, 4.6–13.1) (2012) to 1.7 (0.55–5.31) (2013; P for trend = .001). Risk factors for seroconversion were frequency of injection, homelessness, and history of imprisonment. Injection at least once daily declined from 45.2% to 18.8% (P < .001) and from 36.8% to 26.0% (P = .007) for sharing syringes, and the proportion of undiagnosed HIV infection declined from 84.3% to 15.0% (P < .001). Current OST increased from 12.2% to 27.7% (P < .001), and 48.4% of unlinked seropositive participants were linked to HIV care through 2013. Repeat participants reported higher rates of adequate syringe coverage, linkage to HIV care and OST. Conclusions. Multiple evidence-based interventions delivered through rapid recruitment in a large proportion of the population of PWID are likely to have helped mitigate this HIV outbreak. PMID:28407106

Simplified one-pot synthesis of [.sup.18F]SFB for radiolabeling

DOEpatents

Olma, Sebastian; Shen, Clifton Kwang-Fu

2015-08-04

A non-aqueous single pot synthesis of [.sup.18F]SFB is set forth. The [.sup.18F]SFB produced with this method is then used, for example, to label a peptide or an engineered antibody fragment (diabody) targeting human epidermal growth factor receptor 2 (HER2) as representative examples of labeled compounds for use as an injectable composition to locate abnormal tissue, specifically tumors within an animal or human using a PET scan.

Simplified one-pot synthesis of [.sup.18F]SFB for radiolabeling

DOEpatents

Olma, Sebastian; Shen, Clifton Kwang-Fu

2013-07-16

A non-aqueous single pot synthesis of [.sup.18F]SFB is set forth. The [.sup.18F]SFB produced with this method is then used, for example, to label a peptide or an engineered antibody fragment (diabody) targeting human epidermal growth factor receptor 2 (HER2) as representative examples of labeled compounds for use as an injectable composition to locate abnormal tissue, specifically tumors within an animal or human using a PET scan.

Hepatitis C virus seroprevalence among people who inject drugs and factors associated with infection in eight Russian cities

PubMed Central

2014-01-01

Background Behavioural surveillance among people who inject drugs (PWID) and testing for hepatitis C virus (HCV) and HIV is needed to understand the scope of both epidemics in at-risk populations and to suggest steps to improve their health. Methods PWID were recruited using respondent-driven sampling (RDS) in eight Russian cities. A standardized survey was administered to collect sociodemographic and behavioral information. Blood specimens were obtained for serological testing for HCV and HIV-1. Data across the eight sites were pooled to identify individual-, network-, and city-level factors associated with positive HCV serostatus. Results Among 2,596 PWID participating in the study, 1,837 tested positive for HCV (71%). The sample was 73% male and the mean age was 28. Very few PWID reported regular contact with harm reduction programs. Factors associated with testing positive for HCV were longer duration of injection drug use, testing positive for HIV-1, sharing non-syringe injection paraphernalia and water for rinsing syringes, and larger social network size. Factors negatively associated with HCV-positive serostatus were injecting with a used syringe and two city-level factors: longer mean RDS recruitment chain in a city and higher levels of injecting stimulants. Conclusions HCV prevalence in all eight Russian cities is at the higher end of the range of HCV prevalence among PWID in Europe, which provides evidence that more resources, better prevention programs, and accelerated treatment targeting PWID are needed to control the HCV epidemic. PMID:25253447

Characterization of nZVI mobility in a field scale test.

PubMed

Kocur, Chris M; Chowdhury, Ahmed I; Sakulchaicharoen, Nataphan; Boparai, Hardiljeet K; Weber, Kela P; Sharma, Prabhakar; Krol, Magdalena M; Austrins, Leanne; Peace, Christopher; Sleep, Brent E; O'Carroll, Denis M

2014-01-01

Nanoscale zerovalent iron (nZVI) particles were injected into a contaminated sandy subsurface area in Sarnia, Ontario. The nZVI was synthesized on site, creating a slurry of 1 g/L nanoparticles using the chemical precipitation method with sodium borohydride (NaBH4) as the reductant in the presence of 0.8% wt. sodium carboxymethylcellulose (CMC) polymer to form a stable suspension. Individual nZVI particles formed during synthesis had a transmission electron microscopy (TEM) quantified particle size of 86.0 nm and dynamic light scattering (DLS) quantified hydrodynamic diameter for the CMC and nZVI of 624.8 nm. The nZVI was delivered to the subsurface via gravity injection. Peak normalized total Fe breakthrough of 71% was observed 1m from the injection well and remained above 50% for the 24 h injection period. Samples collected from a monitoring well 1 m from the injection contained nanoparticles with TEM-measured particle diameter of 80.2 nm and hydrodynamic diameter of 562.9 nm. No morphological changes were discernible between the injected nanoparticles and nanoparticles recovered from the monitoring well. Energy dispersive X-ray spectroscopy (EDS) was used to confirm the elemental composition of the iron nanoparticles sampled from the downstream monitoring well, verifying the successful transport of nZVI particles. This study suggests that CMC stabilized nZVI can be transported at least 1 m to the contaminated source zone at significant Fe(0) concentrations for reaction with target contaminants.

Needle and syringe sharing among Iranian drug injectors

PubMed Central

Rafiey, Hassan; Narenjiha, Hooman; Shirinbayan, Peymaneh; Noori, Roya; Javadipour, Morteza; Roshanpajouh, Mohsen; Samiei, Mercedeh; Assari, Shervin

2009-01-01

Objective The role of needle and syringe sharing behavior of injection drug users (IDUs) in spreading of blood-borne infections – specially HIV/AIDS – is well known. However, very little is known in this regard from Iran. The aim of our study was to determine the prevalence and associates of needle and syringe sharing among Iranian IDUs. Methods In a secondary analysis of a sample of drug dependents who were sampled from medical centers, prisons and streets of the capitals of 29 provinces in the Iran in 2007, 2091 male IDUs entered. Socio-demographic data, drug use data and high risk behaviors entered to a logistic regression to determine independent predictors of lifetime needle and syringe sharing. Results 749(35.8%) reported lifetime experience of needle and syringe sharing. The likelihood of lifetime needle and syringe sharing was increased by female gender, being jobless, having illegal income, drug use by family members, pleasure/enjoyment as causes of first injection, first injection in roofless and roofed public places, usual injection at groin, usual injection at scrotum, lifetime experience of nonfatal overdose, and history of arrest in past year and was decreased by being alone at most injections. Conclusion However this data has been extracted from cross-sectional design and we can not conclude causation, some of the introduced variables with association with needle and syringe sharing may be used in HIV prevention programs which target reducing syringe sharing among IDUs. PMID:19643014

Experimental evaluation of the certification-trail method

NASA Technical Reports Server (NTRS)

Sullivan, Gregory F.; Wilson, Dwight S.; Masson, Gerald M.; Itoh, Mamoru; Smith, Warren W.; Kay, Jonathan S.

1993-01-01

Certification trails are a recently introduced and promising approach to fault-detection and fault-tolerance. A comprehensive attempt to assess experimentally the performance and overall value of the method is reported. The method is applied to algorithms for the following problems: huffman tree, shortest path, minimum spanning tree, sorting, and convex hull. Our results reveal many cases in which an approach using certification-trails allows for significantly faster overall program execution time than a basic time redundancy-approach. Algorithms for the answer-validation problem for abstract data types were also examined. This kind of problem provides a basis for applying the certification-trail method to wide classes of algorithms. Answer-validation solutions for two types of priority queues were implemented and analyzed. In both cases, the algorithm which performs answer-validation is substantially faster than the original algorithm for computing the answer. Next, a probabilistic model and analysis which enables comparison between the certification-trail method and the time-redundancy approach were presented. The analysis reveals some substantial and sometimes surprising advantages for ther certification-trail method. Finally, the work our group performed on the design and implementation of fault injection testbeds for experimental analysis of the certification trail technique is discussed. This work employs two distinct methodologies, software fault injection (modification of instruction, data, and stack segments of programs on a Sun Sparcstation ELC and on an IBM 386 PC) and hardware fault injection (control, address, and data lines of a Motorola MC68000-based target system pulsed at logical zero/one values). Our results indicate the viability of the certification trail technique. It is also believed that the tools developed provide a solid base for additional exploration.

Injectable 3-D Fabrication of Medical Electronics at the Target Biological Tissues

NASA Astrophysics Data System (ADS)

Jin, Chao; Zhang, Jie; Li, Xiaokang; Yang, Xueyao; Li, Jingjing; Liu, Jing

2013-12-01

Conventional transplantable biomedical devices generally request sophisticated surgery which however often causes big trauma and serious pain to the patients. Here, we show an alternative way of directly making three-dimensional (3-D) medical electronics inside the biological body through sequential injections of biocompatible packaging material and liquid metal ink. As the most typical electronics, a variety of medical electrodes with different embedded structures were demonstrated to be easily formed at the target tissues. Conceptual in vitro experiments provide strong evidences for the excellent performances of the injectable electrodes. Further in vivo animal experiments disclosed that the formed electrode could serve as both highly efficient ECG (Electrocardiograph) electrode and stimulator electrode. These findings clarified the unique features and practicability of the liquid metal based injectable 3-D fabrication of medical electronics. The present strategy opens the way for directly manufacturing electrophysiological sensors or therapeutic devices in situ via a truly minimally invasive approach.

Message communications of particular message types between compute nodes using DMA shadow buffers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blocksome, Michael A.; Parker, Jeffrey J.

Message communications of particular message types between compute nodes using DMA shadow buffers includes: receiving a buffer identifier specifying an application buffer having a message of a particular type for transmission to a target compute node through a network; selecting one of a plurality of shadow buffers for a DMA engine on the compute node for storing the message, each shadow buffer corresponding to a slot of an injection FIFO buffer maintained by the DMA engine; storing the message in the selected shadow buffer; creating a data descriptor for the message stored in the selected shadow buffer; injecting the datamore » descriptor into the slot of the injection FIFO buffer corresponding to the selected shadow buffer; selecting the data descriptor from the injection FIFO buffer; and transmitting the message specified by the selected data descriptor through the data communications network to the target compute node.« less

Optimization of Injection Molding Parameters for HDPE/TiO2 Nanocomposites Fabrication with Multiple Performance Characteristics Using the Taguchi Method and Grey Relational Analysis

PubMed Central

Pervez, Hifsa; Mozumder, Mohammad S.; Mourad, Abdel-Hamid I.

2016-01-01

The current study presents an investigation on the optimization of injection molding parameters of HDPE/TiO2 nanocomposites using grey relational analysis with the Taguchi method. Four control factors, including filler concentration (i.e., TiO2), barrel temperature, residence time and holding time, were chosen at three different levels of each. Mechanical properties, such as yield strength, Young’s modulus and elongation, were selected as the performance targets. Nine experimental runs were carried out based on the Taguchi L9 orthogonal array, and the data were processed according to the grey relational steps. The optimal process parameters were found based on the average responses of the grey relational grades, and the ideal operating conditions were found to be a filler concentration of 5 wt % TiO2, a barrel temperature of 225 °C, a residence time of 30 min and a holding time of 20 s. Moreover, analysis of variance (ANOVA) has also been applied to identify the most significant factor, and the percentage of TiO2 nanoparticles was found to have the most significant effect on the properties of the HDPE/TiO2 nanocomposites fabricated through the injection molding process. PMID:28773830

Targeted Drug Delivery in the Suprachoroidal Space by Swollen Hydrogel Pushing.

PubMed

Jung, Jae Hwan; Desit, Patcharin; Prausnitz, Mark R

2018-04-01

The purpose is to target model drug particles to the posterior region of the suprachoroidal space (SCS) of the eye controlled via pushing by hydrogel swelling. A particle formulation containing 1% hyaluronic acid (HA) with fluorescent polymer particles and a hydrogel formulation containing 4% HA were introduced in a single syringe as two layers without mixing, and injected sequentially into the SCS of the rabbit eye ex vivo and in vivo using a microneedle. Distribution of particles in the eye was determined by microscopy. During injection, the particle formulation was pushed toward the middle of the SCS by the viscous hydrogel formulation, but less than 12% of particles reached the posterior SCS. After injection, the particle formulation was pushed further toward the macula and optic nerve in the posterior SCS by hydrogel swelling and spreading. Heating the eye to 37°C, or injecting in vivo decreased viscosity and mechanical strength of the hydrogel, thereby allowing it to swell and flow further in the SCS. A high salt concentration (9% NaCl) in the hydrogel formulation further increased hydrogel swelling due to osmotic flow into the hydrogel. In this way, up to 76% of particles were delivered to the posterior SCS from an injection made near the limbus. This study shows that model drug particles can be targeted to the posterior SCS by HA hydrogel swelling and pushing without particle functionalization or administering external driving forces.

Effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis

PubMed Central

Santangeloyz, K.S.; Bertoneyz, A.L.

2011-01-01

summary Objective To ascertain a viral vector-based short hairpin RNA (shRNA) capable of reducing the interleukin-1β (IL-1β) transcript in osteoarthritis (OA)-prone chondrocytes and detect corresponding changes in the expression patterns of several critical disease mediators. Methods Cultured chondrocytes from 2-month-old Hartley guinea pigs were screened for reduction of the IL-1β transcript following plasmid-based delivery of U6-driven shRNA sequences. A successful plasmid/shRNA knockdown combination was identified and used to construct an adeno-associated virus serotype 5 (AAV5) vector for further evaluation. Relative real-time reverse transcription polymerase chain reaction (RTPCR) was used to quantify in vitro transcript changes of IL-1β and an additional nine genes following transduction with this targeting knockdown vector. To validate in vitro findings, this AAV5 vector was injected into one knee, while either an equivalent volume of saline vehicle (three animals) or non-targeting control vector (three animals) were injected into opposite knees. Fold differences and subsequent percent gene expression levels relative to control groups were calculated using the comparative CT (2−ΔΔCT) method. Results Statistically significant decreases in IL-1β expression were achieved by the targeting knockdown vector relative to both the mock-transduced control and non-targeting vector control groups in vitro. Transcript levels of anabolic transforming growth factor-β (TGF-β) were significantly increased by use of this targeting knockdown vector. Transduction with this targeting AAV5 vector also significantly decreased the transcript levels of key inflammatory cytokines [tumor necrosis factor-α (TNF-α), IL-2, IL-8, and IL-12] and catabolic agents [matrix metalloproteinase (MMP)13, MMP2, interferon-γ (IFN-γ), and inducible nitrous oxide synthase (iNOS)] relative to both mock-transduced and non-targeting vector control groups. In vivo application of this targeting knockdown vector resulted in a >50% reduction (P= 0.0045) or >90% (P= 0.0001) of the IL-1β transcript relative to vehicle-only or non-targeting vector control exposed cartilage, respectively. Conclusions Successful reduction of the IL-1β transcript was achieved via RNA interference (RNAi) techniques. Importantly, this alteration significantly influenced the transcript levels of several major players involved in OA pathogenesis in the direction of disease modification. Investigations to characterize additional gene expression changes influenced by targeting knockdown AAV5 vector-based diminution of the IL-1β transcript in vivo are warranted. PMID:21945742

Utilization of the St. Peter Sandstone in the Illinois Basin for CO2 Sequestration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Will, Robert; Smith, Valerie; Leetaru, Hannes

2014-09-30

This project is part of a larger project co-funded by the United States Department of Energy (US DOE) under cooperative agreement DE-FE0002068 from 12/08/2009 through 9/31/2014. The study is to evaluate the potential of formations within the Cambro-Ordovician strata above the Mt. Simon Sandstone as potential targets for carbon dioxide (CO2) sequestration in the Illinois and Michigan Basins. This report evaluates the potential injectivity of the Ordovician St. Peter Sandstone. The evaluation of this formation was accomplished using wireline data, core data, pressure data, and seismic data acquired through funding in this project as well as existing data from twomore » additional, separately funded projects: the US DOE funded Illinois Basin – Decatur Project (IBDP) being conducted by the Midwest Geological Sequestration Consortium (MGSC) in Macon County, Illinois, and the Illinois Industrial Carbon Capture and Sequestration (ICCS) Project funded through the American Recovery and Reinvestment Act (ARRA), which received a phase two award from DOE. This study addresses the question of whether or not the St. Peter Sandstone may serve as a suitable target for CO2 sequestration at locations within the Illinois Basin where it lies at greater depths (below the underground source of drinking water (USDW)) than at the IBDP site. The work performed included numerous improvements to the existing St. Peter reservoir model created in 2010. Model size and spatial resolution were increased resulting in a 3 fold increase in the number of model cells. Seismic data was utilized to inform spatial porosity distribution and an extensive core database was used to develop porosity-permeability relationships. The analysis involved a Base Model representative of the St. Peter at “in-situ” conditions, followed by the creation of two hypothetical models at in-situ + 1,000 feet (ft.) (300 m) and in-situ + 2,000 ft. (600 m) depths through systematic depthdependent adjustment of the Base Model parameters. Properties for the depth shifted models were based on porosity versus depth relationship extracted from the core database followed by application of the porosity-permeability relationship. Each of the three resulting models were used as input to dynamic simulations with the single well injection target of 3.2 million tons per annum (MTPA) for 30 years using an appropriate fracture gradient based bottom hole pressure limit for each injection level. Modeling results are presented in terms of well bottomhole pressure (BHP), injection rate profiles, and three-dimensional (3D) saturation and differential pressure volumes at selected simulation times. Results suggest that the target CO2 injection rate of 3.2 MTPA may be achieved in the St. Peter Sandstone at in-situ conditions and at the in-situ +1,000 ft. (300 m) depth using a single injector well. In the latter case the target injection rate is achieved after a ramp up period which is caused by multi-phase flow effects and thus subject to increased modeling uncertainty. Results confirm that the target rate may not be achieved at the in-situ +2,000 ft. (600 m) level even with multiple wells. These new modeling results for the in-situ case are more optimistic than previous modeling results. This difference is attributed to the difference in methods and data used to develop model permeability distributions. Recommendations for further work include restriction of modeling activity to the in-situ +1,000 ft. (300 m) and shallower depth interval, sensitivity and uncertainty analysis, and refinement of porosity and permeability estimates through depth and area selective querying of the available core database. It is also suggested that further modeling efforts include scope for evaluating project performance in terms of metrics directly related to the Environmental Protection Agency (EPA) Class VI permit requirements for the area of review (AoR) definition and post injection site closure monitoring.« less

Simulation of CO2 Sequestration at Rock Spring Uplift, Wyoming: Heterogeneity and Uncertainties in Storage Capacity, Injectivity and Leakage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng, Hailin; Dai, Zhenxue; Jiao, Zunsheng

2011-01-01

Many geological, geochemical, geomechanical and hydrogeological factors control CO{sub 2} storage in subsurface. Among them heterogeneity in saline aquifer can seriously influence design of injection wells, CO{sub 2} injection rate, CO{sub 2} plume migration, storage capacity, and potential leakage and risk assessment. This study applies indicator geostatistics, transition probability and Markov chain model at the Rock Springs Uplift, Wyoming generating facies-based heterogeneous fields for porosity and permeability in target saline aquifer (Pennsylvanian Weber sandstone) and surrounding rocks (Phosphoria, Madison and cap-rock Chugwater). A multiphase flow simulator FEHM is then used to model injection of CO{sub 2} into the target salinemore » aquifer involving field-scale heterogeneity. The results reveal that (1) CO{sub 2} injection rates in different injection wells significantly change with local permeability distributions; (2) brine production rates in different pumping wells are also significantly impacted by the spatial heterogeneity in permeability; (3) liquid pressure evolution during and after CO{sub 2} injection in saline aquifer varies greatly for different realizations of random permeability fields, and this has potential important effects on hydraulic fracturing of the reservoir rock, reactivation of pre-existing faults and the integrity of the cap-rock; (4) CO{sub 2} storage capacity estimate for Rock Springs Uplift is 6614 {+-} 256 Mt at 95% confidence interval, which is about 36% of previous estimate based on homogeneous and isotropic storage formation; (5) density profiles show that the density of injected CO{sub 2} below 3 km is close to that of the ambient brine with given geothermal gradient and brine concentration, which indicates CO{sub 2} plume can sink to the deep before reaching thermal equilibrium with brine. Finally, we present uncertainty analysis of CO{sub 2} leakage into overlying formations due to heterogeneity in both the target saline aquifer and surrounding formations. This uncertainty in leakage will be used to feed into risk assessment modeling.« less

The Potosi Reservoir Model 2013

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adushita, Yasmin; Smith, Valerie; Leetaru, Hannes

2014-09-30

As a part of a larger project co-funded by the United States Department of Energy (US DOE) to evaluate the potential of formations within the Cambro-Ordovician strata above the Mt. Simon as potential targets for carbon sequestration in the Illinois and Michigan Basins, the Illinois Clean Coal Institute (ICCI) requested Schlumberger to evaluate the potential injectivity and carbon dioxide (CO2) plume size of the Cambrian Potosi Formation. The evaluation of this formation was accomplished using wireline data, core data, pressure data, and seismic data from the US DOE-funded Illinois Basin–Decatur Project (IBDP) being conducted by the Midwest Geological Sequestration Consortiummore » in Macon County, Illinois. In 2010, technical performance evaluations on the Cambrian Potosi Formation were performed through reservoir modeling. The data included formation tops from mud logs, well logs from the VW1 and the CCS1 wells, structural and stratigraphic formation from three dimensional (3D) seismic data, and field data from several waste water injection wells for Potosi Formation. Intention was for two million tons per annum (MTPA) of CO2 to be injected for 20 years. In the preceding, the 2010 Potosi heterogeneous model (referred to as the "Potosi Dynamic Model 2010" in this topical report) was re-run using a new injection scenario; 3.2 MTPA for 30 years. The extent of the Potosi Dynamic Model 2010, however, appeared too small for the new injection target. It was not sufficiently large enough to accommodate the evolution of the plume. The new model, Potosi Dynamic Model 2013a, was built by extending the Potosi Dynamic Model 2010 grid to 30 miles x 30 miles (48.3km x48.3km), while preserving all property modeling workflows and layering. This model was retained as the base case of Potosi Dynamic Model 2013a. The Potosi reservoir model was updated to take into account the new data from the verification well VW2 which was drilled in 2012. The new porosity and permeability modeling was performed to take into account the log data from the new well. Revisions of the 2010 modeling assumptions were also done on relative permeability, capillary pressures, formation water salinity, and the maximum allowable well bottomhole pressure. Dynamic simulations were run using the injection target of 3.2 MTPA for 30 years. This new dynamic model was named Potosi Dynamic Model 2013b. Due to the major uncertainties on the vugs permeability, two models were built; the Pessimistic and Optimistic Cases. The Optimistic Case assumes vugs permeability of 9,000 mD, which is analog to the vugs permeability identified in the pressure fall off test of a waste water injector in the Tuscola site, approx. 40 miles (64.4km) away from the IBDP area. The Pessimistic Case assumes that the vugs permeability is equal to the log data, which does not take into account the permeability from secondary porosity. The probability of such case is deemed low and could be treated as the worst case scenario, since the contribution of secondary porosity to the permeability is neglected and the loss circulation events might correspond to a much higher permeability. It is considered important, however, to identify the range of possible reservoir performance since there are no rigorous data available for the vugs permeability. The Optimistic Case gives an average CO2 injection rate of 0.8 MTPA and cumulative injection of 26 MT in 30 years, which corresponds to 27% of the injection target. The injection rate is approx. 3.2 MTPA in the first year as the well is injecting into the surrounding vugs, and declines rapidly to 0.8 MTPA in year 4 once the surrounding vugs are full and the CO2 start to reach the matrix. This implies that according to this preliminary model, a minimum of four (4) wells could be required to achieve the injection target. This result is lower than the injectivity estimated in the Potosi Dynamic Model 2013a (43 MT in 30 years), since the permeability model applied in the Potosi Dynamic Model 2013b is more conservative. This revision was deemed necessary to treat the uncertainty in a more appropriate manner. As the CO2 follows the paths where vugs interconnection exists, a reasonably large and irregular plume extent was created. For the Optimistic Case, the plume extends 17 miles (27.4km) in E-W and 14 miles (22.5km) in N-S directions after 30 years. After injection is completed, the plume continues to migrate laterally, mainly driven by the remaining pressure gradient. After 100 years post injection, the plume extends 20 miles (32.2km) in E-W and 15.5 miles (24.9km) in N-S directions. Should the targeted cumulative injection of 96 MT be achieved; a much larger plume extent could be expected. For the Optimistic Case, the increase of reservoir pressure at the end of injection is approximately 1200 psia (8,274 kPa) around the injector and gradually decreases away from the well. The reservoir pressure increase is less than 30 psia (206.8 kPa) beyond 14 miles (22.5km) away from injector. Should the targeted cumulative injection of 96 MT be achieved; a much larger areal pressure increase could be expected. The initial reservoir pressure is nearly restored after approximately 100 years post injection. The presence of matrix slows down the pressure dissipations. The Pessimistic Case gives an average CO2 injection rate of 0.2 MTPA and cumulative injection of 7 MT in 30 years, which corresponds to 7% of the injection target. This implies that in the worst case scenario, a minimum of sixteen (16) wells could be required to achieve the injection target. The present evaluation is mainly associated with uncertainty on the vugs permeability, distribution, and interconnectivity. The different results indicated by the Optimistic and Pessimistic Cases signify the importance of vugs permeability characterization. Therefore, injection test and pressure interference test among the wells could be considered to evaluate the local vugs permeability, extent, and interconnectivity. Porosity mapping derived from the seismic inversion could also be used in the succeeding task to characterize the lateral porosity distribution within the reservoir. With or without seismic inversion porosity mapping, it is worth exploring whether increased lateral heterogeneity plays a significant role in Potosi injectivity. Investigations on vugular, dolomitic outcrops suggest that there may be significantly greater lateral heterogeneity than what has been modeled here. Facies modeling within the Potosi has yet to be thoroughly addressed. The carbonates during the time of deposition are believed to be regionally extensive. However, it may be worth delineating the reservoir with other regional wells or modern day analogues to understand the extent of the Potosi. More specifically, the model could incorporate lateral changes or trends if deemed necessary to represent facies transition. Data acquisitions to characterize the fracture pressure gradient, the formation water properties, the relative permeability, and the capillary pressure could also be considered in order to allow a more rigorous evaluation of the Potosi storage performance. A simulation using several injectors could also be considered to determine the required number of wells to achieve the injection target while taking into account the pressure interference.« less

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

PubMed Central

Yoshii, Yukie; Matsumoto, Hiroki; Yoshimoto, Mitsuyoshi; Furukawa, Takako; Morokoshi, Yukie; Sogawa, Chizuru; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2014-01-01

Purpose 64Cu-diacetyl-bis (N 4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with 64Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during 64Cu-ATSM IRT. Methods Biodistribution was evaluated in HT-29 tumor-bearing mice injected with 64Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between 64Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after 64Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic 64Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. Results Penicillamine reduced 64Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after 64Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic 64Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. Conclusions We developed a novel strategy to reduce radiation exposure in critical organs during 64Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other 64Cu-labeled compounds. PMID:24466309

Recent Advance in Liquid Chromatography/Mass Spectrometry Techniques for Environmental Analysis in Japan

PubMed Central

Suzuki, Shigeru

2014-01-01

The techniques and measurement methods developed in the Environmental Survey and Monitoring of Chemicals by Japan’s Ministry of the Environment, as well as a large amount of knowledge archived in the survey, have led to the advancement of environmental analysis. Recently, technologies such as non-target liquid chromatography/high resolution mass spectrometry and liquid chromatography with micro bore column have further developed the field. Here, the general strategy of a method developed for the liquid chromatography/mass spectrometry (LC/MS) analysis of environmental chemicals with a brief description is presented. Also, a non-target analysis for the identification of environmental pollutants using a provisional fragment database and “MsMsFilter,” an elemental composition elucidation tool, is presented. This analytical method is shown to be highly effective in the identification of a model chemical, the pesticide Bendiocarb. Our improved micro-liquid chromatography injection system showed substantially enhanced sensitivity to perfluoroalkyl substances, with peak areas 32–71 times larger than those observed in conventional LC/MS. PMID:26819891

The proper effect site concentration of remifentanil for prevention of myoclonus after etomidate injection

PubMed Central

Ri, Hyun Su; Kim, Tae Kyun; Baik, Seung Wan; Yoon, Ji Uk; Byeon, Gyeong Jo

2011-01-01

Background Etomidate frequently induces myoclonus when administered intravenously with bolus injection during anesthetic induction. This can be bothersome for the anesthesiologist. The dose of remifentanil appropriate for preventing myoclonus without side effects was investigated. Methods All patients with American Society of Anesthesiologists (ASA) physical status I-III were divided into three groups (n = 33 per group) according to the pretreatment effect site concentration of remifentanil (Ultiva, Glaxo-Wellcome, München, Germany) of 0, 2 or 4 ng/ml (Group N: 0 ng/ml, Group R: 2 ng/ml, Group Q: 4 ng/ml) by a target controlled infusion (TCI) system. After a 0.3 mg/kg dose of etomidate was injected intravenously for over 1 minute for anesthetic induction, myoclonus was observed. Before the etomidate injection, the patients were pretreated with remifentanil and their side effects were monitored. Results The number of patients showing myoclonus was significantly different among the groups. The incidence of myoclonus was 81%, 12% and 0% (groups N, R, and Q, respectively, P < 0.01). Side effects including bradycardia and hypotension did not occur in either Group R or Q. Chest wall rigidity occured in 45% of patients in Group Q. Conclusions Administration with a 2 ng/ml effect site concentration of remifentanil could reduce the incidence of myoclonus caused by etomidate bolus injection without chest wall rigidity. PMID:21927682

Efficient generation of knock-in transgenic zebrafish carrying reporter/driver genes by CRISPR/Cas9-mediated genome engineering.

PubMed

Kimura, Yukiko; Hisano, Yu; Kawahara, Atsuo; Higashijima, Shin-ichi

2014-10-08

The type II bacterial CRISPR/Cas9 system is rapidly becoming popular for genome-engineering due to its simplicity, flexibility, and high efficiency. Recently, targeted knock-in of a long DNA fragment via homology-independent DNA repair has been achieved in zebrafish using CRISPR/Cas9 system. This raised the possibility that knock-in transgenic zebrafish could be efficiently generated using CRISPR/Cas9. However, how widely this method can be applied for the targeting integration of foreign genes into endogenous genomic loci is unclear. Here, we report efficient generation of knock-in transgenic zebrafish that have cell-type specific Gal4 or reporter gene expression. A donor plasmid containing a heat-shock promoter was co-injected with a short guide RNA (sgRNA) targeted for genome digestion, a sgRNA targeted for donor plasmid digestion, and Cas9 mRNA. We have succeeded in establishing stable knock-in transgenic fish with several different constructs for 4 genetic loci at a frequency being exceeding 25%. Due to its simplicity, design flexibility, and high efficiency, we propose that CRISPR/Cas9-mediated knock-in will become a standard method for the generation transgenic zebrafish.

Timelines in the management of adrenal crisis - targets, limits and reality.

PubMed

Hahner, Stefanie; Hemmelmann, Nina; Quinkler, Marcus; Beuschlein, Felix; Spinnler, Christina; Allolio, Bruno

2015-04-01

To evaluate current management timelines in adrenal crisis (AC) and to establish time targets and time limits for emergency treatment. Patients from a prospective study who had reported an AC (n = 46) were contacted and asked about management of their AC. A survey among 24 European endocrinologists collected expert recommendations concerning time targets and time limits for contact-arrival time of emergency health professionals and presentation of emergency card-glucocorticoid (GC) injection time. Median time targets and time limits regarded by experts as adequate for contact-arrival time were 45 and 90 min, respectively, and for card-injection time 15 and 30 min, respectively. Thirty-seven of 46 patients could be interviewed. All patients were equipped with an emergency card but only 23 (62%) with an emergency kit. Seven patients (19%) were trained in GC self-injection. The median time interval between contacting a health professional and arrival was 20 min (range 2-2880 min); ≤45 min: n = 32 (86%), <90 min: n = 34 (92%). The median time interval between arrival and administration of GC was 30 min (range 2-2400 min); ≤15 min: n = 17 (46%), ≤30 min: n = 20 (54%). While the time between contacting health professionals and their arrival was within the limits set by experts, initiation of GC administration was delayed in 46% of patients. Thus, improved management of AC needs to focus on shortening the presentation of card-injection time. Given the current reality in the management of AC, promotion of self-injection of GC (s.c. or i.m.) is warranted. © 2014 John Wiley & Sons Ltd.

Systemic RNAi in the small hive beetle Aethina tumida Murray (Coleoptera: Nitidulidae), a serious pest of the European honey bee Apis mellifera.

PubMed

Powell, Michelle E; Bradish, Hannah M; Gatehouse, John A; Fitches, Elaine C

2017-01-01

Aethina tumida is a serious pest of the European honey bee (Apis mellifera) in North America and Australia. Here we investigate whether Laccase 2, the phenoloxidase gene essential for cuticle sclerotisation and pigmentation in many insects, and vacuolar-ATPase V-type subunit A, vital for the generation of proton gradients used to drive a range of transport processes, could be potential targets for RNAi-mediated control of A. tumida. Injection of V-ATPase subunit A (5 ng) and Laccase 2 (12.5 ng) dsRNAs resulted in 100% larval mortality, and qPCR confirmed significant decreases and enhanced suppression of transcript levels over time. Oral delivery of V-ATPase subunit A dsRNA in solutions resulted in 50% mortality; however, gene suppression could not be verified. We suggest that the inconsistent RNAi effect was a consequence of dsRNA degradation within the gut owing to the presence of extracellular nucleases. Target specificity was confirmed by a lack of effect on survival or gene expression in honey bees injected with A. tumida dsRNAs. This is the first study to show evidence for systemic RNAi in A. tumida in response to injected dsRNA, but further research is required to develop methods to induce RNAi effects via ingestion. © 2016 Crown copyright. Pest Management Science © 2016 Society of Chemical Industry. © 2016 Crown copyright. Pest Management Science © 2016 Society of Chemical Industry.

Preparation study of indocyanine green-rituximab: A new receptor-targeted tracer for sentinel lymph node in breast cancer

PubMed Central

Cong, Bin-Bin; Sun, Xiao; Song, Xian-Rang; Liu, Yan-Bing; Zhao, Tong; Cao, Xiao-Shan; Qiu, Peng-Fei; Tian, Chong-Lin

2016-01-01

An appropriate receptor-targeted tracer for sentinel lymph node biopsy (SLNB) was prepared. We combined the fluorescence tracer (Indocyanine green, ICG) with Rituximab (a chimeric human/murine monoclonal antibody targeting the CD20 antigen on the surface of lymphocyte) directly to produce a new tracer (ICG-Rituximab). When the new tracer drains to the lymph node, Rituximab will combine with CD20 receptor on the B-cell surface in the lymph node. If the statue of antibody-receptor connection does not reach saturation, the number of Rituximab is less than CD20. With this appropriate injection dose, the new tracer could only stay in sentinel lymph node (SLN) and make it imaging. Positive fluorescence SLN was detected 12 minutes after injection with no other organs imaging. The imaging of SLN was stable and clear for 20–24 hours. Due to SLN stained with more ICG than the lymphatic vessel, the fluorescence situation of SLN would be brighter than the vessel. The surgeon can detect the positive fluorescence SLN easily without following the fluorescence imaging lymphatic vessel. The results of our preliminary study showed that the new tracer might be useful for improving SLN imaging and worth further clinical study. SLNB with the new tracer could be a convenient method for detecting SLN and would become a standard performance in clinical practice. PMID:27374088

Preparation study of indocyanine green-rituximab: A new receptor-targeted tracer for sentinel lymph node in breast cancer.

PubMed

Cong, Bin-Bin; Sun, Xiao; Song, Xian-Rang; Liu, Yan-Bing; Zhao, Tong; Cao, Xiao-Shan; Qiu, Peng-Fei; Tian, Chong-Lin; Yu, Jin-Ming; Wang, Yong-Sheng

2016-07-26

An appropriate receptor-targeted tracer for sentinel lymph node biopsy (SLNB) was prepared. We combined the fluorescence tracer (Indocyanine green, ICG) with Rituximab (a chimeric human/murine monoclonal antibody targeting the CD20 antigen on the surface of lymphocyte) directly to produce a new tracer (ICG-Rituximab). When the new tracer drains to the lymph node, Rituximab will combine with CD20 receptor on the B-cell surface in the lymph node. If the statue of antibody-receptor connection does not reach saturation, the number of Rituximab is less than CD20. With this appropriate injection dose, the new tracer could only stay in sentinel lymph node (SLN) and make it imaging. Positive fluorescence SLN was detected 12 minutes after injection with no other organs imaging. The imaging of SLN was stable and clear for 20-24 hours. Due to SLN stained with more ICG than the lymphatic vessel, the fluorescence situation of SLN would be brighter than the vessel. The surgeon can detect the positive fluorescence SLN easily without following the fluorescence imaging lymphatic vessel. The results of our preliminary study showed that the new tracer might be useful for improving SLN imaging and worth further clinical study. SLNB with the new tracer could be a convenient method for detecting SLN and would become a standard performance in clinical practice.

Preliminary experiments of a single x-ray view catheter 3D localization algorithm for targeted stem cell injections

NASA Astrophysics Data System (ADS)

Iovea, M.; Creed, J.; Perin, E.; Neagu, M.; Mateiasi, G.

2009-02-01

The aim of this study was to conduct a preliminary check of a new method for measuring the 3D catheter position based on only one X-Ray view (image) and a simple pre-calibration procedure for catheters that could be equipped with high-opacity equal-spaced markers. The application chosen for this experiment is the targeted delivery of cell based therapeutic via a transendocardial retrograde approach into the left ventricle. This approach has shown promising therapeutic retention data when injected directly into the myocardial tissue, but lacks in the ability of the user to confidently manipulate the catheter within the left ventricle cavity space under traditional fluoroscopic guidance using a needle based catheter. The need for a new technique arose from the potential for increased safety and therapeutic efficacy by improving the targeting of the agent. The new technique, destined for Image guided catheter navigation systems for cardiac interventions, is based on a measurement of the marker's size and distance between them and followed by a comparison with the referenced catheter position. Preliminary experiments made with a simple phantom are presented, emphasizing the ability of the new technique in measuring the markers and the catheter tip 3D position. An overall maximum error in positioning markers and catheter tip below 12% has been obtained, yielding a promising result for continuing the future work of improving the algorithm accuracy.

Optimatization of transient transformation methods to study gene expression in Musa acuminata (AAA group) cultivar Ambon Lumut

NASA Astrophysics Data System (ADS)

Prayuni, Kinasih; Dwivany, Fenny M.

2015-09-01

Banana is classified as a climateric fruit, whose ripening is regulated by ethylene. Ethylene is synthesized from ACC (1-aminocyclopropane-1-carboxylic acid) by ACC oxidase enzyme which is encoded by ACO gene. Controling an important gene expression in ethylene biosynthesis pathway has became a target to delay the ripening process. Therefore in the previous study we have designed a MaACO-RNAi construct to control MaACO gene expression. In this research, we study the effectiveness of different transient transformation methods to deliver the construct. Direct injection, with or no vaccum infiltration methods were used to deliver MaACO-RNAi construct. All of the methods succesfully deliver the construct into banana fruits based on RT-PCR result.

PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time.

PubMed

Kooijmans, S A A; Fliervoet, L A L; van der Meel, R; Fens, M H A M; Heijnen, H F G; van Bergen En Henegouwen, P M P; Vader, P; Schiffelers, R M

2016-02-28

Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, the therapeutic applicability of EVs may be limited due to a lack of cell-targeting specificity and rapid clearance of exogenous EVs from the circulation. In order to improve EV characteristics for drug delivery to tumor cells, we have developed a novel method for decorating EVs with targeting ligands conjugated to polyethylene glycol (PEG). Nanobodies specific for the epidermal growth factor receptor (EGFR) were conjugated to phospholipid (DMPE)-PEG derivatives to prepare nanobody-PEG-micelles. When micelles were mixed with EVs derived from Neuro2A cells or platelets, a temperature-dependent transfer of nanobody-PEG-lipids to the EV membranes was observed, indicative of a 'post-insertion' mechanism. This process did not affect EV morphology, size distribution, or protein composition. After introduction of PEG-conjugated control nanobodies to EVs, cellular binding was compromised due to the shielding properties of PEG. However, specific binding to EGFR-overexpressing tumor cells was dramatically increased when EGFR-specific nanobodies were employed. Moreover, whereas unmodified EVs were rapidly cleared from the circulation within 10min after intravenous injection in mice, EVs modified with nanobody-PEG-lipids were still detectable in plasma for longer than 60min post-injection. In conclusion, we propose post-insertion as a novel technique to confer targeting capacity to isolated EVs, circumventing the requirement to modify EV-secreting cells. Importantly, insertion of ligand-conjugated PEG-derivatized phospholipids in EV membranes equips EVs with improved cell specificity and prolonged circulation times, potentially increasing EV accumulation in targeted tissues and improving cargo delivery. Copyright © 2015. Published by Elsevier B.V.

Integration and evaluation of a needle-positioning robot with volumetric microcomputed tomography image guidance for small animal stereotactic interventions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waspe, Adam C.; McErlain, David D.; Pitelka, Vasek

Purpose: Preclinical research protocols often require insertion of needles to specific targets within small animal brains. To target biologically relevant locations in rodent brains more effectively, a robotic device has been developed that is capable of positioning a needle along oblique trajectories through a single burr hole in the skull under volumetric microcomputed tomography (micro-CT) guidance. Methods: An x-ray compatible stereotactic frame secures the head throughout the procedure using a bite bar, nose clamp, and ear bars. CT-to-robot registration enables structures identified in the image to be mapped to physical coordinates in the brain. Registration is accomplished by injecting amore » barium sulfate contrast agent as the robot withdraws the needle from predefined points in a phantom. Registration accuracy is affected by the robot-positioning error and is assessed by measuring the surface registration error for the fiducial and target needle tracks (FRE and TRE). This system was demonstrated in situ by injecting 200 {mu}m tungsten beads into rat brains along oblique trajectories through a single burr hole on the top of the skull under micro-CT image guidance. Postintervention micro-CT images of each skull were registered with preintervention high-field magnetic resonance images of the brain to infer the anatomical locations of the beads. Results: Registration using four fiducial needle tracks and one target track produced a FRE and a TRE of 96 and 210 {mu}m, respectively. Evaluation with tissue-mimicking gelatin phantoms showed that locations could be targeted with a mean error of 154{+-}113 {mu}m. Conclusions: The integration of a robotic needle-positioning device with volumetric micro-CT image guidance should increase the accuracy and reduce the invasiveness of stereotactic needle interventions in small animals.« less

Antithrombotic Therapy in Neonates and Children

PubMed Central

Monagle, Paul; Chan, Anthony K. C.; Goldenberg, Neil A.; Ichord, Rebecca N.; Journeycake, Janna M.; Nowak-Göttl, Ulrike

2012-01-01

Background: Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. Methods: The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Results: We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). Conclusions: The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies. PMID:22315277

Epidemiology of hepatitis C virus exposure in Egypt: Opportunities for prevention and evaluation

PubMed Central

Miller, F DeWolfe; Elzalabany, Mahmoud S; Hassani, Sara; Cuadros, Diego F

2015-01-01

AIM: To critically evaluate the current epidemiology data on exposures, rather than infection, to hepatitis C virus (HCV) transmission and recommend epidemiologic strategies to fill gaps. METHODS: Standard methods for identifying and evaluating relevant epidemiologic literature and available data were used. RESULTS: There is a large body of literature on the epidemiology of HCV transmission in Egypt that collectively identifies ongoing iatrogenic exposures as the major driver for HCV transmission due to short comings in infection control and standard procedures. Additional epidemiologic studies on HCV transmission that requires the participation of human subject is unwarranted. Alternatively, very little literature was found on the epidemiology of exposure to HCV, infection control, and safe injection practices. The information that is available on patterns of HCV exposure shows high frequencies of inadequate infection control, problems in sterilization in health care facilities, low rates of hand washing, untrained personnel, lack of stated policies in facilities, HCV contamination of instruments and very large injection frequencies with low but very significant syringe and needle reuse. There is an important need to increase the number, size, and diversity of epidemiologic studies on HCV exposures, patterns of risk factors for infection, infection control, and safe injection practices. In addition to health care facilities evaluation, relevant knowledge attitude and practice studies are recommended. CONCLUSION: Epidemiologic methods on HCV exposure can be used to characterize the magnitude of exposures to HCV infection, target interventions to reduce exposures, and provide the best method for evaluating interventions by demonstrating the reduction of exposure to HCV infection. PMID:26668697

An in-situ stimulation experiment in crystalline rock - assessment of induced seismicity levels during stimulation and related hazard for nearby infrastructure

NASA Astrophysics Data System (ADS)

Gischig, Valentin; Broccardo, Marco; Amann, Florian; Jalali, Mohammadreza; Esposito, Simona; Krietsch, Hannes; Doetsch, Joseph; Madonna, Claudio; Wiemer, Stefan; Loew, Simon; Giardini, Domenico

2016-04-01

A decameter in-situ stimulation experiment is currently being performed at the Grimsel Test Site in Switzerland by the Swiss Competence Center for Energy Research - Supply of Electricity (SCCER-SoE). The underground research laboratory lies in crystalline rock at a depth of 480 m, and exhibits well-documented geology that is presenting some analogies with the crystalline basement targeted for the exploitation of deep geothermal energy resources in Switzerland. The goal is to perform a series of stimulation experiments spanning from hydraulic fracturing to controlled fault-slip experiments in an experimental volume approximately 30 m in diameter. The experiments will contribute to a better understanding of hydro-mechanical phenomena and induced seismicity associated with high-pressure fluid injections. Comprehensive monitoring during stimulation will include observation of injection rate and pressure, pressure propagation in the reservoir, permeability enhancement, 3D dislocation along the faults, rock mass deformation near the fault zone, as well as micro-seismicity. The experimental volume is surrounded by other in-situ experiments (at 50 to 500 m distance) and by infrastructure of the local hydropower company (at ~100 m to several kilometres distance). Although it is generally agreed among stakeholders related to the experiments that levels of induced seismicity may be low given the small total injection volumes of less than 1 m3, detailed analysis of the potential impact of the stimulation on other experiments and surrounding infrastructure is essential to ensure operational safety. In this contribution, we present a procedure how induced seismic hazard can be estimated for an experimental situation that is untypical for injection-induced seismicity in terms of injection volumes, injection depths and proximity to affected objects. Both, deterministic and probabilistic methods are employed to estimate that maximum possible and the maximum expected induced earthquake magnitude. Deterministic methods are based on McGarr's upper limit for the maximum induced seismic moment. Probabilistic methods rely on estimates of Shapiro's seismogenic index and seismicity rates from past stimulation experiments that are scaled to injection volumes of interest. Using rate-and-state frictional modelling coupled to a hydro-mechanical fracture flow model, we demonstrate that large uncontrolled rupture events are unlikely to occur and that deterministic upper limits may be sufficiently conservative. The proposed workflow can be applied to similar injection experiments, for which hazard to nearby infrastructure may limit experimental design.

Inertial fusion energy target injection, tracking, and beam pointing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Petzoldt, Ronald Wayne

1995-03-07

Several cryogenic targets must be injected each second into a reaction chamber. Required target speed is about 100 m/s. Required accuracy of the driver beams on target is a few hundred micrometers. Fuel strength is calculated to allow acceleration in excess of 10,000 m/s 2 if the fuel temperature is less than 17 K. A 0.1 μm thick dual membrane will allow nearly 2,000 m/s 2 acceleration. Acceleration is gradually increased and decreased over a few membrane oscillation periods (a few ms), to avoid added stress from vibrations which could otherwise cause a factor of two decrease in allowed acceleration.more » Movable shielding allows multiple targets to be in flight toward the reaction chamber at once while minimizing neutron heating of subsequent targets. The use of multiple injectors is recommended for redundancy which increases availability and allows a higher pulse rate. Gas gun, rail gun, induction accelerator, and electrostatic accelerator target injection devices are studied, and compared. A gas gun is the preferred device for indirect-drive targets due to its simplicity and proven reliability. With the gas gun, the amount of gas required for each target (about 10 to 100 mg) is acceptable. A revolver loading mechanism is recommended with a cam operated poppet valve to control the gas flow. Cutting vents near the muzzle of the gas gun barrel is recommended to improve accuracy and aid gas pumping. If a railgun is used, we recommend an externally applied magnetic field to reduce required current by an order of magnitude. Optical target tracking is recommended. Up/down counters are suggested to predict target arrival time. Target steering is shown to be feasible and would avoid the need to actively point the beams. Calculations show that induced tumble from electrostatically steering the target is not excessive.« less

Ultrasound-guided corticosteroid injection of the subtalar joint for treatment of juvenile idiopathic arthritis.

PubMed

Young, Cody M; Horst, Deanna M; Murakami, James W; Shiels, William E

2015-07-01

The subtalar joint is commonly affected in children with juvenile idiopathic arthritis and is challenging to treat percutaneously. To describe the technique for treating the subtalar joint with US-guided corticosteroid injections in children and young adults with juvenile idiopathic arthritis and to evaluate the safety of the treatment. We retrospectively analyzed 122 patients (age 15 months-29 years) with juvenile idiopathic arthritis who were referred by a pediatric rheumatologist for corticosteroid injection therapy for symptoms related to the hindfoot or ankle. In these patients the diseased subtalar joint was targeted for therapy, often in conjunction with adjacent affected joints or tendon sheaths of the ankle. We used a protocol based on age, weight and joint for triamcinolone hexacetonide or triamcinolone acetonide dose prescription. We describe the technique for successful treatment of the subtalar joint. A total of 241 subtalar joint corticosteroid injections were performed under US guidance, including 68 repeat injections for recurrent symptoms in 26 of the 122 children and young adults. The average time interval between repeat injections was 24.8 months (range 2.2-130.7 months, median 14.2 months). Subcutaneous tissue atrophy and skin hypopigmentation were the primary complications observed. These complications occurred in 3.9% of the injections. With appropriate training and practice, the subtalar joint can be reliably and safely targeted with US-guided corticosteroid injection to treat symptoms related to juvenile idiopathic arthritis.

Parallel momentum input by tangential neutral beam injections in stellarator and heliotron plasmas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, S., E-mail: nishimura.shin@lhd.nifs.ac.jp; Nakamura, Y.; Nishioka, K.

The configuration dependence of parallel momentum inputs to target plasma particle species by tangentially injected neutral beams is investigated in non-axisymmetric stellarator/heliotron model magnetic fields by assuming the existence of magnetic flux-surfaces. In parallel friction integrals of the full Rosenbluth-MacDonald-Judd collision operator in thermal particles' kinetic equations, numerically obtained eigenfunctions are used for excluding trapped fast ions that cannot contribute to the friction integrals. It is found that the momentum inputs to thermal ions strongly depend on magnetic field strength modulations on the flux-surfaces, while the input to electrons is insensitive to the modulation. In future plasma flow studies requiringmore » flow calculations of all particle species in more general non-symmetric toroidal configurations, the eigenfunction method investigated here will be useful.« less

Particle beam injection system

DOEpatents

Jassby, Daniel L.; Kulsrud, Russell M.

1977-01-01

This invention provides a poloidal divertor for stacking counterstreaming ion beams to provide high intensity colliding beams. To this end, method and apparatus are provided that inject high energy, high velocity, ordered, atomic deuterium and tritium beams into a lower energy, toroidal, thermal equilibrium, neutral, target plasma column that is magnetically confined along an endless magnetic axis in a strong restoring force magnetic field having helical field lines to produce counterstreaming deuteron and triton beams that are received bent, stacked and transported along the endless axis, while a poloidal divertor removes thermal ions and electrons all along the axis to increase the density of the counterstreaming ion beams and the reaction products resulting therefrom. By balancing the stacking and removal, colliding, strong focused particle beams, reaction products and reactions are produced that convert one form of energy into another form of energy.

Targeted organ generation using Mixl1-inducible mouse pluripotent stem cells in blastocyst complementation.

PubMed

Kobayashi, Toshihiro; Kato-Itoh, Megumi; Nakauchi, Hiromitsu

2015-01-15

Generation of functional organs from patients' own cells is one of the ultimate goals of regenerative medicine. As a novel approach to creation of organs from pluripotent stem cells (PSCs), we employed blastocyst complementation in organogenesis-disabled animals and successfully generated PSC-derived pancreas and kidneys. Blastocyst complementation, which exploits the capacity of PSCs to participate in forming chimeras, does not, however, exclude contribution of PSCs to the development of tissues-including neural cells or germ cells-other than those specifically targeted by disabling of organogenesis. This fact provokes ethical controversy if human PSCs are to be used. In this study, we demonstrated that forced expression of Mix-like protein 1 (encoded by Mixl1) can be used to guide contribution of mouse embryonic stem cells to endodermal organs after blastocyst injection. We then succeeded in applying this method to generate functional pancreas in pancreatogenesis-disabled Pdx1 knockout mice using a newly developed tetraploid-based organ-complementation method. These findings hold promise for targeted organ generation from patients' own PSCs in livestock animals.

Evaluation of Lithofacies Up-Scaling Methods for Probabilistic Prediction of Carbon Dioxide Behavior

NASA Astrophysics Data System (ADS)

Park, J. Y.; Lee, S.; Lee, Y. I.; Kihm, J. H.; Kim, J. M.

2017-12-01

Behavior of carbon dioxide injected into target reservoir (storage) formations is highly dependent on heterogeneities of geologic lithofacies and properties. These heterogeneous lithofacies and properties basically have probabilistic characteristics. Thus, their probabilistic evaluation has to be implemented properly into predicting behavior of injected carbon dioxide in heterogeneous storage formations. In this study, a series of three-dimensional geologic modeling is performed first using SKUA-GOCAD (ASGA and Paradigm) to establish lithofacies models of the Janggi Conglomerate in the Janggi Basin, Korea within a modeling domain. The Janggi Conglomerate is composed of mudstone, sandstone, and conglomerate, and it has been identified as a potential reservoir rock (clastic saline formation) for geologic carbon dioxide storage. Its lithofacies information are obtained from four boreholes and used in lithofacies modeling. Three different up-scaling methods (i.e., nearest to cell center, largest proportion, and random) are applied, and lithofacies modeling is performed 100 times for each up-scaling method. The lithofacies models are then compared and analyzed with the borehole data to evaluate the relative suitability of the three up-scaling methods. Finally, the lithofacies models are converted into coarser lithofacies models within the same modeling domain with larger grid blocks using the three up-scaling methods, and a series of multiphase thermo-hydrological numerical simulation is performed using TOUGH2-MP (Zhang et al., 2008) to predict probabilistically behavior of injected carbon dioxide. The coarser lithofacies models are also compared and analyzed with the borehole data and finer lithofacies models to evaluate the relative suitability of the three up-scaling methods. Three-dimensional geologic modeling, up-scaling, and multiphase thermo-hydrological numerical simulation as linked methodologies presented in this study can be utilized as a practical probabilistic evaluation tool to predict behavior of injected carbon dioxide and even to analyze its leakage risk. This work was supported by the Korea CCS 2020 Project of the Korea Carbon Capture and Sequestration R&D Center (KCRC) funded by the National Research Foundation (NRF), Ministry of Science and ICT (MSIT), Korea.

DNA Nanocarriers for Systemic Administration: Characterization and In Vivo Bioimaging in Healthy Mice

PubMed Central

David, Stephanie; Passirani, Catherine; Carmoy, Nathalie; Morille, Marie; Mevel, Mathieu; Chatin, Benoit; Benoit, Jean-Pierre; Montier, Tristan; Pitard, Bruno

2013-01-01

We hereby present different DNA nanocarriers consisting of new multimodular systems (MMS), containing the cationic lipid dioleylaminesuccinylparomomycin (DNA MMS DOSP), or bis (guanidinium)-tren-cholesterol (DNA MMS BGTC), and DNA lipid nanocapsules (DNA LNCs). Active targeting of the asialoglycoprotein receptor (ASGP-R) using galactose as a ligand for DNA MMS (GAL DNA MMS) and passive targeting using a polyethylene glycol coating for DNA LNCs (PEG DNA LNCs) should improve the properties of these DNA nanocarriers. All systems were characterized via physicochemical methods and the DNA payload of DNA LNCs was quantified for the first time. Afterwards, their biodistribution in healthy mice was analyzed after encapsulation of a fluorescent dye via in vivo biofluorescence imaging (BFI), revealing various distribution profiles depending on the cationic lipid used and their surface characteristics. Furthermore, the two vectors with the best prolonged circulation profile were administered twice in healthy mice revealing that the new DNA MMS DOSP vectors showed no toxicity and the same distribution profile for both injections, contrary to PEG DNA LNCs which showed a rapid clearance after the second injection, certainly due to the accelerated blood clearance phenomenon. PMID:23299832

Botulinum toxin-A injections via electrical motor point stimulation to treat writer's cramp: pilot study.

PubMed

Lim, E C H; Quek, A M L; Seet, R C S

2006-06-30

Writer's cramp describes a task-specific dystonia, in which the act of writing initiates dystonic posturing of the hands. Previous studies have described the efficacy of injections of botulinum toxin type-A (BTX-A) under electromyographic guidance, in which the injected muscle is either voluntarily, or less often, electrically (electrical motor point stimulation, EMPS) activated to ensure that the needle is in the target muscle. We performed an open label, prospective study to assess the efficacy of BTX-A injections, performed with EMPS under electromyographic guidance. Eight patients (seven male and one female) of mean age 44 (range 25-66) were recruited. All had idiopathic writer's cramp. Outcome measures, which included timed writing, objective assessment of dystonia (modified Ashworth scale and a visual analog scale rating) and patient assessment of functional disability, were assessed before injections and at six weeks follow-up. The total dose of BTX-A injected for writer's cramp ranged from 50 to 130 units, which was less than that reported in previous studies using muscle activation techniques (up to 300 units). Improvements were observed in all outcome measures. Patients reported mild (non-disabling) weakness of injected, but not of uninjected muscles. Lower dosages of BTX-A, administered using EMPS, offers the advantages of decreased cost and increased accuracy of targeting, while achieving good outcomes.

CRISPR-mediated direct mutation of cancer genes in the mouse liver

PubMed Central

Xue, Wen; Chen, Sidi; Yin, Hao; Tammela, Tuomas; Papagiannakopoulos, Thales; Joshi, Nikhil S.; Cai, Wenxin; Yang, Gillian; Bronson, Roderick; Crowley, Denise G.; Zhang, Feng; Anderson, Daniel G.; Sharp, Phillip A.; Jacks, Tyler

2014-01-01

The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem (ES) cells1. Here we describe a new method of cancer model generation using the CRISPR/Cas system in vivo in wild-type mice. We have used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs)2–4 to the liver and directly target the tumor suppressor genes Pten5 and p536, alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology7, 8. Simultaneous targeting of Pten and p53 induced liver tumors that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumor tissue revealed insertion or deletion (indel) mutations of the tumor suppressor genes, including bi-allelic mutations of both Pten and p53 in tumors. Furthermore, co-injection of Cas9 plasmids harboring sgRNAs targeting the β-Catenin gene (Ctnnb1) and a single-stranded DNA (ssDNA) oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-Catenin. This study demonstrates the feasibility of direct mutation of tumor suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics. PMID:25119044

MicroRNA and dsRNA targeting chitin synthase A reveal a great potential for pest management of the hemipteran insect Nilaparvata lugens.

PubMed

Li, Tengchao; Chen, Jie; Fan, Xiaobin; Chen, Weiwen; Zhang, Wenqing

2017-07-01

Two RNA silencing pathways in insects are known to exist that are mediated by short interfering RNAs (siRNAs) and microRNAs (miRNAs), which have been hypothesised to be promising methods for insect pest control. However, a comparison between miRNA and siRNA in pest control is still unavailable, particularly in targeting chitin synthase gene A (CHSA). The dsRNA for Nilaparvata lugens CHSA (dsNlCHSA) and the microR-2703 (miR-2703) mimic targeting NlCHSA delivered via feeding affected the development of nymphs, reduced their chitin content and led to lethal phenotypes. The protein level of NlCHSA was downregulated after female adults were injected with dsNlCHSA or the miR-2703 mimic, but there were no significant differences in vitellogenin (NlVg) expression or in total oviposition relative to the control group. However, 90.68 and 46.13% of the eggs laid by the females injected with dsNlCHSA and miR-2703 mimic were unable to hatch, respectively. In addition, a second-generation miRNA and RNAi effect on N. lugens was observed. Ingested miR-2703 seems to be a good option for killing N. lugens nymphs, while NlCHSA may be a promising target for RNAi-based pest management. These findings provide important evidence for applications of small non-coding RNAs (snRNAs) in insect pest management. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

CRISPR-mediated direct mutation of cancer genes in the mouse liver.

PubMed

Xue, Wen; Chen, Sidi; Yin, Hao; Tammela, Tuomas; Papagiannakopoulos, Thales; Joshi, Nikhil S; Cai, Wenxin; Yang, Gillian; Bronson, Roderick; Crowley, Denise G; Zhang, Feng; Anderson, Daniel G; Sharp, Phillip A; Jacks, Tyler

2014-10-16

The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the β-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.

A laser syringe aimed at delivering drug into the outer layer of human skin

NASA Astrophysics Data System (ADS)

Yoh, Jack J.; Jang, Hun-jae; Park, Mi-ae; Han, Tae-hee; Hah, Jung-moo

2012-07-01

A desire to eliminate hypodermic needle in transdermal drug delivery may now be realized. Imaging of the skin after injection of fluorescent probe and biotin via the bio-ballistic technique revealed the epidermal and dermal layers which were stained well below 60 μm underneath the abdominal skin of the guinea-pig. An extensive network of cells are shown in the deeper layer of the stained dermis as the distributed fluorescein isothiocyanate (FITC) dose is administered by repeated injection via the laser-based microjet. Here, we show our method of laser-based microjet drug delivery is capable of breaching guinea-pig's skin tissue and then delivering controlled dose of drug to the targeted region between 10 to 400 μm underneath the outermost layer of the skin. While minimizing pain and tissue damage by reducing the injection volume to ˜100 nl per pulse and the microjet diameter of half the conventional syringe needle in 100 μm, the optimally controlled delivery of liquid drug by the irradiated laser pulse is shown possible.

Hot air injection for removal of dense, non-aqueous-phase liquid contaminants from low-permeability soils

DOE Office of Scientific and Technical Information (OSTI.GOV)

Payne, F.C.

1996-08-01

The performance of soil vapor extraction systems for the recovery of volatile and semi-volatile organic compounds is potentially enhanced by the injection of heated air to increase soil temperatures. The soil temperature increase is expected to improve soil vapor extraction (SVE) performance by increasing target compound vapor pressures and by increasing soil permeability through drying. The vapor pressure increase due to temperature rise relieves the vapor pressure limit on the feasibility of soil vapor extraction. However, the system still requires an air flow through the soil system to deliver heat and to recover mobilized contaminants. Although the soil permeability canmore » be increased through drying, very low permeability soils and low permeability soils adjacent to high permeability air flow pathways will be treated slowly, if at all. AR thermal enhancement methods face this limitation. Heated air injection offers advantages relative to other thermal techniques, including low capital and operation costs. Heated air injection is at a disadvantage relative to other thermal techniques due to the low heat capacity of air. To be effective, heated air injection requires that higher air flows be established than for steam injection or radio frequency heating. Heated air injection is not economically feasible for the stratified soil system developed as a standard test for this document. This is due to the inability to restrict heated air flow to the clay stratum when a low-resistance air flow pathway is available in the adjoining sand. However, the technology should be especially attractive, both technically and economically, for low-volatile contaminant recovery from relatively homogeneous soil formations. 16 refs., 2 tabs.« less

Cost and Performance Assessment of In-situ Chemical Oxidation for Intermittent and Continuous Oxidant Injection

NASA Astrophysics Data System (ADS)

Kim, U.; Parker, J.; Borden, R. C.

2015-12-01

In situ chemical oxidation (ISCO) is a popular remediation technology that involves injection of chemical oxidant into groundwater to destroy dissolved and non-aqueous liquid phase contaminants. Depending on site conditions, oxidant can be injected into the contaminated subsurface periodically (intermittently) or continuously. A common approach is to intermittently inject oxidant into a network of wells over a period long enough to emplace oxidant over a target treatment volume (referred to ISCO-int). The injection phase is followed by a passive phase when the oxidant is allowed to react with contaminants and natural oxygen demand (NOD) and to migrate under natural hydraulic gradients. This process may be repeated multiple times until termination criteria are met. Recently, some practitioners have adopted an alternative approach in which oxidant is injected continuously with extraction wells recovering unreacted oxidant to recycle with additional makeup oxidant to maintain its constant concentration (referred to ISCO-cont). Each method has certain advantages and disadvantages. This study numerically evaluates those two ISCO practices in terms of remediation costs and performance based on multiple equi-probable parameter sets. Stochastic cost optimization toolbox (SCOToolkit) is used for this purpose. SCOToolkit is an integrated semi-analytical model for contaminant transport and remediation (e.g., thermal source treatment, ISCO, electron donor injections, permeable reactive barriers) enabling inverse solution and Monte Carlo simulations. Four different aquifer settings, slow and fast Darcy velocities combined with low and high NOD conditions, are used for the evaluation. Preliminary results showed that ISCO-cont is effective for a full scale application without large investment while ISCO-int is more efficient to utilize oxidant in well-characterized sites. Pros and cons of each approach are discussed for the practical use of ISCO for various site conditions.

Social and Structural Factors Associated with HIV Infection among Female Sex Workers Who Inject Drugs in the Mexico-US Border Region

PubMed Central

Strathdee, Steffanie A.; Lozada, Remedios; Martinez, Gustavo; Vera, Alicia; Rusch, Melanie; Nguyen, Lucie; Pollini, Robin A.; Uribe-Salas, Felipe; Beletsky, Leo; Patterson, Thomas L.

2011-01-01

Background FSWs who inject drugs (FSW-IDUs) can acquire HIV through high risk sexual and injection behaviors. We studied correlates of HIV infection among FSW-IDUs in northern Mexico, where sex work is quasi-legal and syringes can be legally obtained without a prescription. Methods FSW-IDUs>18 years old who reported injecting drugs and recent unprotected sex with clients in Tijuana and Ciudad Juarez underwent surveys and HIV/STI testing. Logistic regression identified correlates of HIV infection. Results Of 620 FSW-IDUs, prevalence of HIV, gonorrhea, Chlamydia, trichomonas, syphilis titers ≥1∶8, or any of these infections was 5.3%, 4%, 13%, 35%, 10% and 72%, respectively. Compared to other FSW-IDUs, HIV-positive women were more likely to: have syphilis titers ≥1∶8 (36% vs. 9%, p<0.001), often/always inject drugs with clients (55% vs. 32%, p = 0.01), and experience confiscation of syringes by police (49% vs. 28%, p = 0.02). Factors independently associated with HIV infection were syphilis titers ≥1∶8, often/always injecting with clients and police confiscation of syringes. Women who obtained syringes from NEPs (needle exchange programs) within the last month had lower odds of HIV infection associated with active syphilis, but among non-NEP attenders, the odds of HIV infection associated with active syphilis was significantly elevated. Conclusions Factors operating in both the micro-social environment (i.e., injecting drugs with clients) and policy environment (i.e., having syringes confiscated by police, attending NEPs) predominated as factors associated with risk of HIV infection, rather than individual-level risk behaviors. Interventions should target unjustified policing practices, clients' risk behaviors and HIV/STI prevention through NEPs. PMID:21541349

End-tidal concentration of sevoflurane for preventing rocuronium-induced withdrawal of the arm in pediatric patients.

PubMed

Yeom, Jong Hoon; Kim, Yong Oh; Lee, Jae Min; Jeon, Woo Jae

2014-04-01

During induction of general anesthesia, the intravenous injection of rocuronium is often associated with withdrawal movement of the arm due to pain, and this abrupt withdrawal may result in dislodgement of the venous catheter, injury, or inadequate injection of rocuronium. We performed this study to evaluate the 50 and 95% effective end-tidal concentrations of sevoflurane (ETsev) for preventing rocuronium-induced withdrawal of the arm. We conducted a prospective double-blind study in 31 pediatric patients. After free flow of lactated Ringer's IV fluid was confirmed, anesthesia was induced in the patients by using 2.5% thiopental sodium (4 mg/kg) and sevoflurane (4 vol%) with 6 L/min of oxygen. When the target ETsev was reached, preservative-free 1% lidocaine (1.5 mg/kg) was intravenously injected during manual venous occlusion and rocuronium (0.6 mg/kg) was injected after lidocaine injection under free-flow intravenous fluid. A nurse who was an investigator and was blinded to the ETsev injected the rocuronium. The nurse evaluated the response. Non-withdrawal movement was observed in 5 out of 11 patients with ETsev 3.0 vol% and in 5 out of 6 patients with ETsev 3.5 vol%. By Dixon's up-and-down method, the 50% effective concentration (EC50) of sevoflurane for non-withdrawal movement at rocuronium injection was 3.1 ± 0.4 vol%. A logistic regression curve of the probability of non-withdrawal movements showed that the 50% effective ETsev for abolishing withdrawal movement at rocuronium injection was 2.9 vol% (95% confidence interval [CI] 2.4-3.8 vol%) and the 95% effective ETsev was 4.3 vol% (95% CI 3.6-9.8 vol%). This study showed that the 50 and 95% effective ETsev that prevent withdrawal movement at rocuronium injection are 2.9 and 4.3 vol%, respectively.

A radiopaque polymer hydrogel used as a fiducial marker in gynecologic-cancer patients receiving brachytherapy

PubMed Central

Bair, Ryan J.; Bair, Eric; Viswanathan, Akila N.

2016-01-01

PURPOSE We assessed a novel Food and Drug Administration–approved hydrogel, synthesized as absorbable iodinated particles, in gynecologic-cancer patients undergoing computed tomography (CT) or magnetic resonance (MR) based brachytherapy after external beam radiation. METHODS AND MATERIALS Nineteen patients underwent CT-guided (n = 13) or MR-guided (n = 6) brachytherapy for gynecologic cancers. Seventy-seven hydrogel injections were placed. The hydrogel material was injected into gross residual disease and/or key anatomic landmarks in amounts ranging from 0.1 to 0.4 mL. The visibility of the tracer was scored on CT and on MR images using a 5-point scoring scale. A Cohen’s kappa statistic was calculated to assess interobserver agreement. To assess the unadjusted effects of baseline parameters on hydrogel visibility, we modeled visibility using a linear mixed-effect model. RESULTS Injections were without complication. The kappa statistic was 0.77 (95% confidence interval [CI], 0.68–0.87). The volume of hydrogel injected was significantly associated with visibility on both CT (p = 0.032) and magnetic resonance imaging (p = 0.016). We analyzed visibility by location, controlling for amount. A 0.1-cc increase in volume injected was associated with increases of 0.54 (95% CI = 0.05–1.03) in the CT visibility score and 0.83 (95% CI = 0.17–1.49) in the MR visibility score. Injection of 0.4 cc or more was required for unequivocal visibility on CT or MR. No statistically significant correlation was found between tumor type, tumor location, or anatomical location of injection and visibility on either CT or magnetic resonance imaging. CONCLUSIONS In this first report of an injectable radiopaque hydrogel, targets were visualized to assist with three-dimensional–based brachytherapy in gynecologic malignancies. This marker has potential for several applications, is easy to inject and visualize, and caused no acute complications. PMID:26481393

Financial methods for waterflooding injectate design

DOEpatents

Heneman, Helmuth J.; Brady, Patrick V.

2017-08-08

A method of selecting an injectate for recovering liquid hydrocarbons from a reservoir includes designing a plurality of injectates, calculating a net present value of each injectate, and selecting a candidate injectate based on the net present value. For example, the candidate injectate may be selected to maximize the net present value of a waterflooding operation.

A Comparative Study of Drug Delivery Methods Targeted to the Mouse Inner Ear: Bullostomy Versus Transtympanic Injection

PubMed Central

Cediel, Rafael; Celaya, Adelaida M.; Lassaletta, Luis; Varela-Nieto, Isabel; Contreras, Julio

2017-01-01

We present two minimally invasive microsurgical techniques in rodents for specific drug delivery into the middle ear so that it may reach the inner ear. The first procedure consists of perforation of the tympanic bulla, termed bullostomy; the second one is a transtympanic injection. Both emulate human clinical intratympanic procedures. Chitosan-glycerophosphate (CGP) and Ringer´s Lactate buffer (RL) were used as biocompatible vehicles for local drug delivery. CGP is a nontoxic biodegradable polymer widely used in pharmaceutical applications. It is a viscous liquid at RT but it congeals to a semi solid phase at body temperature. RL is an isotonic solution used for intravenous administrations in humans. A small volume of this vehicle is precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The safety profiles of both techniques were studied and compared by using functional and morphological tests. Hearing was evaluated by registering the Auditory Brainstem Response (ABR) before and several times after microsurgery. The cytoarchitecture and preservation level of cochlear structures were studied by conventional histological techniques in paraformaldehyde-fixed and decalcified cochlear samples. In parallel, unfixed cochlear samples were taken and immediately frozen to analyze gene expression profiles of inflammatory markers by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Both procedures are suitable as drug delivery methods into the mouse middle ear, although transtympanic injection proved to be less invasive compared to bullostomy. PMID:28362376

Enhancement of tumor-to-nontumor localization ratios by hepatocyte-directed blood clearance of antibodies labeled with certain residualizing radiolabels.

PubMed

Patel, S; Stein, R; Ong, G L; Goldenberg, D M; Mattes, M J

1999-08-01

To increase tumor-to-nontumor localization ratios of injected radiolabeled antibodies (Abs), several interrelated methods were used. The model systems used were two human carcinoma xenografts grown in nude mice, targeted by antibodies RS11 (antiepithelial glycoprotein-2) or MN-14 (anticarcinoembryonic antigen). The Abs were conjugated with biotin and 111In-benzyl diethylenetriamine pentaacetic acid, and, at various times after injection, were cleared by intraperitoneal injection of galactosylated streptavidin, which delivers the complexes to hepatocytes. The radiolabel used was selected because it is retained within tumors after catabolism of the Ab by the tumor cell but is quite rapidly excreted from hepatocytes into bile. With blood clearance induced at 24 h, and dissection 5 h later, high tumor-to-nontumor ratios were attained. Depending on the model used, tumor-to-blood ratios were 16:1 to 31:1, and tumor-to-nontumor ratios for the kidney, lungs and bone were also high and greatly increased by the clearance regimen. Despite clearance into the liver, tumor-to-liver ratios remained >1, due to fairly rapid biliary excretion of the label. The absolute antibody uptake by the tumors was also high, because 24 h was allowed for the Ab to penetrate and bind to cells within the subcutaneous tumors. The method described produced high tumor-to-nontumor ratios at 1 d after injection and may be advantageous for tumor imaging with antibodies. Radiation dosimetry calculations indicate that there is only a slight advantage with this approach for radioimmunotherapy.

Quantifying cancer cell receptors with paired-agent fluorescent imaging: a novel method to account for tissue optical property effects

NASA Astrophysics Data System (ADS)

Sadeghipour, Negar; Davis, Scott C.; Tichauer, Kenneth M.

2018-02-01

Dynamic fluorescence imaging approaches can be used to estimate the concentration of cell surface receptors in vivo. Kinetic models are used to generate the final estimation by taking the targeted imaging agent concentration as a function of time. However, tissue absorption and scattering properties cause the final readout signal to be on a different scale than the real fluorescent agent concentration. In paired-agent imaging approaches, simultaneous injection of a suitable control imaging agent with a targeted one can account for non-specific uptake and retention of the targeted agent. Additionally, the signal from the control agent can be a normalizing factor to correct for tissue optical property differences. In this study, the kinetic model used for paired-agent imaging analysis (i.e., simplified reference tissue model) is modified and tested in simulation and experimental data in a way that accounts for the scaling correction within the kinetic model fit to the data to ultimately extract an estimate of the targeted biomarker concentration.

Private algorithms for the protected in social network search

PubMed Central

Kearns, Michael; Roth, Aaron; Wu, Zhiwei Steven; Yaroslavtsev, Grigory

2016-01-01

Motivated by tensions between data privacy for individual citizens and societal priorities such as counterterrorism and the containment of infectious disease, we introduce a computational model that distinguishes between parties for whom privacy is explicitly protected, and those for whom it is not (the targeted subpopulation). The goal is the development of algorithms that can effectively identify and take action upon members of the targeted subpopulation in a way that minimally compromises the privacy of the protected, while simultaneously limiting the expense of distinguishing members of the two groups via costly mechanisms such as surveillance, background checks, or medical testing. Within this framework, we provide provably privacy-preserving algorithms for targeted search in social networks. These algorithms are natural variants of common graph search methods, and ensure privacy for the protected by the careful injection of noise in the prioritization of potential targets. We validate the utility of our algorithms with extensive computational experiments on two large-scale social network datasets. PMID:26755606

Private algorithms for the protected in social network search.

PubMed

Kearns, Michael; Roth, Aaron; Wu, Zhiwei Steven; Yaroslavtsev, Grigory

2016-01-26

Motivated by tensions between data privacy for individual citizens and societal priorities such as counterterrorism and the containment of infectious disease, we introduce a computational model that distinguishes between parties for whom privacy is explicitly protected, and those for whom it is not (the targeted subpopulation). The goal is the development of algorithms that can effectively identify and take action upon members of the targeted subpopulation in a way that minimally compromises the privacy of the protected, while simultaneously limiting the expense of distinguishing members of the two groups via costly mechanisms such as surveillance, background checks, or medical testing. Within this framework, we provide provably privacy-preserving algorithms for targeted search in social networks. These algorithms are natural variants of common graph search methods, and ensure privacy for the protected by the careful injection of noise in the prioritization of potential targets. We validate the utility of our algorithms with extensive computational experiments on two large-scale social network datasets.

An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting: The importance of selective blood-brain barrier uptake.

PubMed

Bode, Gerard H; Coué, Gregory; Freese, Christian; Pickl, Karin E; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C; Tziveleka, Leto-Aikaterini; Sideratou, Zili; Engbersen, Johan F J; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J G; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M; Kirkpatrick, C James; Steinbusch, Harry W M; Frank, Hans-Georg; Unger, Ronald E; Martinez-Martinez, Pilar

2017-04-01

Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood-brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial barriers shows great potential as a therapeutic strategy in a wide variety of diseases. Functionalizing nanoparticles with peptides allows for more efficient targeting to specific organs. We have evaluated the hemocompatibilty, cytotoxicity, endothelial uptake, efficacy of delivery and safety of liposome, hyperbranched polyester, poly(glycidol) and acrylamide-based nanoparticles functionalized with peptides targeting brain endothelial receptors, in vitro and in vivo. We used an ELISA-based method for the detection of nanoparticles in biological fluids, investigating the blood clearance rate and in vivo biodistribution of labeled nanoparticles in the brain after intravenous injection in Wistar rats. Herein, we provide a detailed report of in vitro and in vivo observations. Copyright © 2016 Elsevier Inc. All rights reserved.

Homing of the Stem Cells from the Acupoint ST-36 to the Site of a Spinal Cord Injury: A Preliminary Study.

PubMed

Jung, Sharon Jiyoon; Kook, Myung Geun; Kim, Sungchul; Kang, Kyung-Sun; Soh, Kwang-Sup

2018-06-04

Homing of stem cells (SCs) to desired targets such as injured tissues remains a lingering problem in cell-based therapeutics. Studies on the biodistribution of intravenously administered SCs have shown the inefficacy of blood vessels as the homing path because most of the injected SCs are captured in the capillary beds of the lungs. We considered an alternative administration method utilizing the acupuncture meridians or the primo vascular system (PVS). We injected SCs at the acupoint Zusanli (ST-36) below the knee of a nude mouse with a spinal cord injured at the thoracic T9-10 vertebrae. The SCs migrated from the ST-36, along the sciatic nerve, the lumbar 4-5, and then the spinal cord to the injury point T9-10. The SCs were not randomly scattered but were rather well aligned like marathon race runners, along the PVS route toward the injury point. We observed the SCs at 1, 3, 6, 9, 12, and 15 hours after injection. The fast runners among the injected SCs took about 6 hours to reach the sciatic nerve, about 9 hours to reach the lumbar 4-5 and about 15 hours to reach the injury point T9-10. Copyright © 2018. Published by Elsevier B.V.

Superior Recess Access of the Lumbar Facet Joint.

PubMed

Demir-Deviren, Sibel; Singh, Sukhminder; Hanelin, Joshua

2017-04-01

Descriptive approach to accessing the lumbar facet joint by superior recess. This study is aimed to describe an approach to accessing the lumbar facet joint through targeting the superior recess during lumbar facet joint injections. Lumbar facet joint injections are routinely performed for both the diagnosis and treatment of chronic low back pain. Previous studies either did not specify which part of the joint to target, or recommended targeting the inferior aspect of the joint to access the inferior recess. One study did mention the superior recess as an alternative to injecting the inferior recess, but none has focused on description of the technique. This is the first time this technique has been described. The records and fluoroscopic images were reviewed for all patients over a period of 9 months (January-September 2012) using the proposed technique. This resulted in a total of 48 patients; 15 men, 29 women, and a total of 117 facet joint intra-articular injections. Among these 48 patients, injections were repeated in total of 4 cases. The average time of injections among 4 repeat cases was 121 days. The success of the procedure was confirmed with an arthrogram demonstrating contrast flowing from the superior recess inferiorly through the joint space. Successful access of the lumbar facet joint through puncture of the superior recess was seen in 114 cases, with 3 unsuccessful attempts to enter facet joints due to osteophytes at involved levels. There were no complications observed during the procedure. We find this approach to be highly successful, safe, and well tolerated by the patient and recommend it as a technique for access of the lumbar facet joint in those patients in whom direct puncture of the inferior recess is difficult.

Enhanced tunability of the composition in silicon oxynitride thin films by the reactive gas pulsing process

NASA Astrophysics Data System (ADS)

Aubry, Eric; Weber, Sylvain; Billard, Alain; Martin, Nicolas

2014-01-01

Silicon oxynitride thin films were sputter deposited by the reactive gas pulsing process. Pure silicon target was sputtered in Ar, N2 and O2 mixture atmosphere. Oxygen gas was periodically and solely introduced using exponential signals. In order to vary the injected O2 quantity in the deposition chamber during one pulse at constant injection time (TON), the tau mounting time τmou of the exponential signals was systematically changed for each deposition. Taking into account the real-time measurements of the discharge voltage and the I(O*)/I(Ar*) emission lines ratio, it is shown that the oscillations of the discharge voltage during the TON and TOFF times (injection of O2 stopped) are attributed to the preferential adsorption of the oxygen compared to that of the nitrogen. The sputtering mode alternates from a fully nitrided mode (TOFF time) to a mixed mode (nitrided and oxidized mode) during the TON time. For the highest injected O2 quantities, the mixed mode tends toward a fully oxidized mode due to an increase of the trapped oxygen on the target. The oxygen (nitrogen) concentration in the SiOxNy films similarly (inversely) varies as the oxygen is trapped. Moreover, measurements of the contamination speed of the Si target surface are connected to different behaviors of the process. At low injected O2 quantities, the nitrided mode predominates over the oxidized one during the TON time. It leads to the formation of Si3N4-yOy-like films. Inversely, the mixed mode takes place for high injected O2 quantities and the oxidized mode prevails against the nitrided one producing SiO2-xNx-like films.

The use of solid lipid nanoparticles to target a lipophilic molecule to the liver after intravenous administration to mice.

PubMed

Lu, Wen; He, Lang Chong; Wang, Chang He; Li, Yan Hua; Zhang, San Qi

2008-10-01

Taspine solid lipid nanoparticles (Ta-SLN) and taspine solid lipid nanoparticles modified by galactoside (Ta-G2SLN) were prepared by the film evaporation-extrusion method. The nanoparticles were spherical or near-spherical particles with smooth surface, small size and high encapsulation efficiency. Ta-G2SLN and Ta-SLN showed significant inhibition on 7721 cell growth. Intravenous injection of either Ta-SLN or Ta-G2SLN resulted in a higher plasma and liver concentration and a longer retention time in mice compared with the administration of Ta. These results suggested that SLN tended to be preferentially delivered to the liver and Ta-G2SLN may further enhance liver targeting.

Targeting the Mevalonate Pathway to Reduce Mortality from Ovarian Cancer

DTIC Science & Technology

2015-10-01

intraperitoneal (i.p.) injection twice weekly; atorvastatin (10 mg/kg per injection) was i.p. administered daily (19). Tumor Translational Relevance Recent...other lipophilic statins exerted an anti- tumor phenotype, we assessed another inhibitor of HMG-CoA reductase, atorvastatin (Brand name: Lipitor), in an...OVCAR5 tumor xenograft model. Daily injections of atorvastatin (10 mg/kg) led to significantly reduced tumor sizes as compared with vehicle control

Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles.

PubMed

Kim, Yoo Chun; Oh, Kyung Hee; Edelhauser, Henry F; Prausnitz, Mark R

2015-09-01

In this work, we tested the hypothesis that particles injected into the suprachoroidal space can be localized at the site of injection or broadly distributed throughout the suprachoroidal space by controlling polymeric formulation properties. Single hollow microneedles were inserted into the sclera of New Zealand White rabbits and injected non-biodegradable fluorescently tagged nanoparticles and microparticles suspended in polymeric formulations into the suprachoroidal space of the eye. When formulated in saline, the particles were distributed over 29-42% of the suprachoroidal space immediately after injection. To spread particles over larger areas of the choroidal surface, addition of hyaluronic acid to make moderately non-Newtonian solutions increased particle spread to up to 100% of the suprachoroidal space. To localize particles at the site of injection adjacent to the ciliary body, strongly non-Newtonian polymer solutions localized particles to 8.3-20% of the suprachoroidal space, which exhibited a small increase in area over the course of two months. This study demonstrates targeted particle delivery within the suprachoroidal space using polymer formulations that spread particles over the whole choroidal surface or localized them adjacent to the ciliary body after injection. Copyright © 2015 Elsevier B.V. All rights reserved.

Microfluidic Device for Sequential Injection and Flushing of Solutions and its Application to Immunosensing

NASA Astrophysics Data System (ADS)

Nashida, Norihiro; Suzuki, Hiroaki

A microfluidic system with injecting and flushing functions was developed. In the system, hydrophilic flow channels have a dry-film photoresist layer which facilitates the introduction of solutions from four injection ports. The injection and flushing of solutions are controlled by valves operated by electrowetting. The valves consist of gold working electrodes in the flow channels or a through-hole in the glass substrate. Solutions can be sequentially introduced through the injection ports into a reaction chamber and flushed through a valve in the through-hole. Necessary immunoassay steps can be conducted on the chip, and a target antibody can be detected electrochemically.

Surface-downhole and crosshole geoelectrics for monitoring of brine injection at the Ketzin CO2 storage site

NASA Astrophysics Data System (ADS)

Rippe, Dennis; Bergmann, Peter; Labitzke, Tim; Wagner, Florian; Schmidt-Hattenberger, Cornelia

2016-04-01

The Ketzin pilot site in Germany is the longest operating on-shore CO2 storage site in Europe. From June 2008 till August 2013, a total of ˜67,000 tonnes of CO2 were safely stored in a saline aquifer at depths of 630 m to 650 m. The storage site has now entered the abandonment phase, and continuation of the multi-disciplinary monitoring as part of the national project "CO2 post-injection monitoring and post-closure phase at the Ketzin pilot site" (COMPLETE) provides the unique chance to participate in the conclusion of the complete life cycle of a CO2 storage site. As part of the continuous evaluation of the functionality and integrity of the CO2 storage in Ketzin, from October 12, 2015 till January 6, 2015 a total of ˜2,900 tonnes of brine were successfully injected into the CO2 reservoir, hereby simulating in time-lapse the natural backflow of brine and the associated displacement of CO2. The main objectives of this brine injection experiment include investigation of how much of the CO2 in the pore space can be displaced by brine and if this displacement of CO2 during the brine injection differs from the displacement of formation fluid during the initial CO2 injection. Geophysical monitoring of the brine injection included continuous geoelectric measurements accompanied by monitoring of pressure and temperature conditions in the injection well and two adjacent observation wells. During the previous CO2 injection, the geoelectrical monitoring concept at the Ketzin pilot site consisted of permanent crosshole measurements and non-permanent large-scale surveys (Kiessling et al., 2010). Time-lapse geoelectrical tomographies derived from the weekly crosshole data at near-wellbore scale complemented by six surface-downhole surveys at a scale of 1.5 km showed a noticeable resistivity signature within the target storage zone, which was attributed to the CO2 plume (Schmidt-Hattenberger et al., 2011) and interpreted in terms of relative CO2 and brine saturations (Bergmann et al., 2012). During the brine injection, usage of a new data acquisition unit allowed the daily collection of an extended crosshole data set. This data set was complemented by an alternative surface-downhole acquisition geometry, which for the first time allowed for regular current injections from three permanent surface electrodes into the existing electrical resistivity downhole array without the demand of an extensive field survey. This alternative surface-downhole acquisition geometry is expected to be characterized by good data quality and well confined sensitivity to the target storage zone. Time-lapse geoelectrical tomographies have been derived from both surface-downhole and crosshole data and show a conductive signature around the injection well associated with the displacement of CO2 by the injected brine. In addition to the above mentioned objectives of this brine injection experiment, comparative analysis of the surface-downhole and crosshole data provides the opportunity to evaluate the alternative surface-downhole acquisition geometry with respect to its resolution within the target storage zone and its ability to quantitatively constrain the displacement of CO2 during the brine injection. These results will allow for further improvement of the deployed alternative surface-downhole acquisition geometries. References Bergmann, P., Schmidt-Hattenberger, C., Kiessling, D., Rücker, C., Labitzke, T., Henninges, J., Baumann, G., Schütt, H. (2012). Surface-Downhole Electrical Resistivity Tomography applied to Monitoring of the CO2 Storage Ketzin (Germany). Geophysics, 77, B253-B267. Kiessling, D., Schmidt-Hattenberger, C., Schuett, H., Schilling, F., Krueger, K., Schoebel, B., Danckwardt, E., Kummerow, J., CO2SINK Group (2010). Geoelectrical methods for monitoring geological CO2 storage: First results from cross-hole and surface-downhole measurements from the CO2SINK test site at Ketzin (Germany). International Journal of Greenhouse Gas Control, 4(5), 816-826. Schmidt-Hattenberger, C., Bergmann, P., Kießling, D., Krüger, K., Rücker, C., Schütt, H., Ketzin Group (2011). Application of a Vertical Electrical Resistivity Array (VERA) for monitoring CO2 migration at the Ketzin site: First performance evaluation. Energy Procedia, 4, 3363-3370.

Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

NASA Astrophysics Data System (ADS)

Kim, Sung Eun; Zhang, Li; Ma, Kai; Riegman, Michelle; Chen, Feng; Ingold, Irina; Conrad, Marcus; Turker, Melik Ziya; Gao, Minghui; Jiang, Xuejun; Monette, Sebastien; Pauliah, Mohan; Gonen, Mithat; Zanzonico, Pat; Quinn, Thomas; Wiesner, Ulrich; Bradbury, Michelle S.; Overholtzer, Michael

2016-11-01

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

Methods and Variables Associated with the Risk of Septic Arthritis Following Intra-Articular Injections in Horses: A Survey of Veterinarians.

PubMed

Gillespie, Caroline C; Adams, Stephen B; Moore, George E

2016-11-01

To determine common methods for intra-articular injections and variables associated with the risk of septic arthritis following intra-articular injection in the horse. Cross-sectional survey. Equine veterinarians. A link to an online survey was distributed to equine practitioners in 2014. Responses for descriptive data were tabulated. Data on infection rates obtained from medical records were analyzed. Variables associated with the risk of septic arthritis were determined using χ 2 or Fisher's exact tests and logistic regression. Common current methods for intra-articular injections were determined from 241 surveys. Sixty-four of 241 surveys (26.6%) contained data with numbers of joints injected and number of infections obtained from review of medical records. Eight different injection methods were used by more than 2/3 of responding veterinarians. A total of 67 out of 319,760 injected joints reported became septic following injection, giving an incidence of 2.10 septic joints per 10,000 intra-articular injections. Based on multivariate analysis, infection rates were significantly lower when veterinarians prepared their own injection sites (OR=0.10) and had <20 years of practice experience (OR=0.025), whereas infection rates were significantly higher when hair was removed at the injection site (OR=19.70). There is a low incidence of septic arthritis following intra-articular injection and a large number of injection methods reported by responding veterinarians. The low reported incidence of infection may be related to the large number of practitioners frequently using common methods. © Copyright 2016 by The American College of Veterinary Surgeons.

Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

PubMed

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

2015-01-01

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

[Radioimmunoimaging of lymphoma in mice with a two-step pretargeting strategy using biotinyled CD45 monoclonal antibody and (188)Re-avidin].

PubMed

Li, Guiping; Zheng, Wenli; Huang, Baodan; DU, Li; Qi, Yongshuai; Huang, Kai; Zhang, Hui

2015-08-01

To establish a two-step pretargeting approach to lymphoma radioimmunoimaging in mice using biotinynaled CD45 monoclonal antibody (McAb) and (188)Re-avidin in a tumor-bearing mouse model. Six Nod-Scid mice bearing lymphoma cell xenograft were randomized to receive either an intravenous injection of 50 µg/200 µL biotinyled CD45 McAb followed 24 h later by an intraperitoneal injection of 3.7 MBq (50 µg/100 µL) (188)Re-avidin (two-step pretargeting group), or a single intravenous injection of 3.7 MBq (100 µg/100 µL) (188)Re-CD45 McAb (control group). SPECT was performed at 0.5, 1, 6 and 23 h post-injection to characterize (188)Re isotope biodistribution. At 24 h pos-injection, the mice were sacrificed for measurement of radioactivity uptake in the tumor and normal tissues and calculation of the tumor-to-non-tumor (T/NT) ratios. SPECT showed that the two-step pretargeting method resulted in a low radioactivity in the blood pool during the imaging and a concentrated radioactivity in the liver and spleen. The transplanted tumor began to be displayed at 1 h post-injection and was clearly displayed at 1-6 h; the images were clear even at 23 h. With the two-step pretargeting method, the radioactive uptake at 24 h post-injection were (1.34∓0.52)%, (6.77∓2.32)%, and (2.81∓1.25)% in the tumor, kidney and liver, respectively, with low radioactivity levels in other organs and high tumor/blood and tumor/muscle ratios (4.28∓0.82 and 8.00∓0.88, respectively). In the control group, SPECT revealed intense radioactivity in the liver, spleen, and kidneys with obscure display of the tumor; at 20 h, the radioactivity in the blood pool remained high but that in the tumor was low, and the tumor/blood and tumor/muscle ratios at 24 h were only 0.58∓0.06 and 3.21∓0.24, respectively. Compared with (188)Re-CD45 McAb, the two-step pretargeting approach exhibits a good specificity in targeting lymphoma with an increased T/NT ratio in mice and allows early tumor display at 1 h post-injection.

In vivo near-infrared imaging of fibrin deposition in thromboembolic stroke in mice.

PubMed

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa-targeted near-infrared fluorescence (NIRF) imaging. The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke.

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma.

PubMed

Ge, Yaoqi; Zhong, Yuejiao; Ji, Guozhong; Lu, Qianling; Dai, Xinyu; Guo, Zhirui; Zhang, Peng; Peng, Gang; Zhang, Kangzhen; Li, Yuntao

2018-01-01

To study the characterization of Fe3O4@Au-C225 composite targeted MNPs. Fe3O4@Au-C225 was prepared by the absorption method. The immunosorbent assay was used to evaluate its absorption efficiency at C225 Fc. ZETA SIZER3000 laser particle size analyzer, ultraviolet photometer and its characteristics were analyzed by VSM. the targeting effect of Fe3O4@Au-C225 composite targeted MNPs on U251 cells in vitro were detected by 7.0 Tesla Micro-MR; and subcutaneous transplanted human glioma in nude mice were performed the targeting effect in vivo after tail vein injection of Fe3O4@Au-C225 composite targeted MNPs by MRI. The self-prepared Fe3O4@Au composite MNPs can adsorb C225 with high efficiency of adsorption so that Fe3O4@Au-C225 composite targeted MNPs were prepared successfully. Fe3O4@Au-C225 composite targeted MNPs favorably targeted human glioma cell line U251 in vitro; Fe3O4@Au-C225 composite targeted MNPs have good targeting ability to xenografted glioma on nude mice in vivo, and can be traced by MRI. The Fe3O4@Au-C225 composite targeted MNPs have the potential to be used as a tracer for glioma in vivo.

Randomized trial of anesthetic methods for intravitreal injections.

PubMed

Blaha, Gregory R; Tilton, Elisha P; Barouch, Fina C; Marx, Jeffrey L

2011-03-01

To compare the effectiveness of four different anesthetic methods for intravitreal injection. Twenty-four patients each received four intravitreal injections using each of four types of anesthesia (proparacaine, tetracaine, lidocaine pledget, and subconjunctival injection of lidocaine) in a prospective, masked, randomized block design. Pain was graded by the patient on a 0 to 10 scale for both the anesthesia and the injection. The average combined pain scores for both the anesthesia and the intravitreal injection were 4.4 for the lidocaine pledget, 3.5 for topical proparacaine, 3.8 for the subconjunctival lidocaine injection, and 4.1 for topical tetracaine. The differences were not significant (P = 0.65). There were also no statistical differences in the individual anesthesia or injection pain scores. Subconjunctival lidocaine injection had the most side effects. Topical anesthesia is an effective method for limiting pain associated with intravitreal injections.

Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins.

PubMed

Quadros, Rolen M; Miura, Hiromi; Harms, Donald W; Akatsuka, Hisako; Sato, Takehito; Aida, Tomomi; Redder, Ronald; Richardson, Guy P; Inagaki, Yutaka; Sakai, Daisuke; Buckley, Shannon M; Seshacharyulu, Parthasarathy; Batra, Surinder K; Behlke, Mark A; Zeiner, Sarah A; Jacobi, Ashley M; Izu, Yayoi; Thoreson, Wallace B; Urness, Lisa D; Mansour, Suzanne L; Ohtsuka, Masato; Gurumurthy, Channabasavaiah B

2017-05-17

Conditional knockout mice and transgenic mice expressing recombinases, reporters, and inducible transcriptional activators are key for many genetic studies and comprise over 90% of mouse models created. Conditional knockout mice are generated using labor-intensive methods of homologous recombination in embryonic stem cells and are available for only ~25% of all mouse genes. Transgenic mice generated by random genomic insertion approaches pose problems of unreliable expression, and thus there is a need for targeted-insertion models. Although CRISPR-based strategies were reported to create conditional and targeted-insertion alleles via one-step delivery of targeting components directly to zygotes, these strategies are quite inefficient. Here we describe Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR), a targeting strategy in which long single-stranded DNA donors are injected with pre-assembled crRNA + tracrRNA + Cas9 ribonucleoprotein (ctRNP) complexes into mouse zygotes. We show for over a dozen loci that Easi-CRISPR generates correctly targeted conditional and insertion alleles in 8.5-100% of the resulting live offspring. Easi-CRISPR solves the major problem of animal genome engineering, namely the inefficiency of targeted DNA cassette insertion. The approach is robust, succeeding for all tested loci. It is versatile, generating both conditional and targeted insertion alleles. Finally, it is highly efficient, as treating an average of only 50 zygotes is sufficient to produce a correctly targeted allele in up to 100% of live offspring. Thus, Easi-CRISPR offers a comprehensive means of building large-scale Cre-LoxP animal resources.

[Comparative study on four kinds of assessment methods of post-marketing safety of Danhong injection].

PubMed

Li, Xuelin; Tang, Jinfa; Meng, Fei; Li, Chunxiao; Xie, Yanming

2011-10-01

To study the adverse reaction of Danhong injection with four kinds of methods, central monitoring method, chart review method, literature study method and spontaneous reporting method, and to compare the differences between them, explore an appropriate method to carry out post-marketing safety evaluation of traditional Chinese medicine injection. Set down the adverse reactions' questionnaire of four kinds of methods, central monitoring method, chart review method, literature study method and collect the information on adverse reactions in a certain period. Danhong injection adverse reaction information from Henan Province spontaneous reporting system was collected with spontaneous reporting method. Carry on data summary and descriptive analysis. Study the adverse reaction of Danhong injection with four methods of central monitoring method, chart review method, literature study method and spontaneous reporting method, the rates of adverse events were 0.993%, 0.336%, 0.515%, 0.067%, respectively. Cyanosis, arrhythmia, hypotension, sweating, erythema, hemorrhage dermatitis, rash, irritability, bleeding gums, toothache, tinnitus, asthma, elevated aminotransferases, constipation, pain are new discovered adverse reactions. The central monitoring method is the appropriate method to carry out post-marketing safety evaluation of traditional Chinese medicine injection, which could objectively reflect the real world of clinical usage.

Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

PubMed

Berglund, A K; Schnabel, L V

2017-07-01

Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Experimental controlled study. Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. This study examined MSC death in vitro only and utilized antisera from a small number of horses. The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death. © 2016 The Authors Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.

Blood-Derived Smooth Muscle Cells as a Target for Gene Delivery

PubMed Central

Yang, Zhe; Shao, Hongwei; Tan, Yaohong; Eton, Darwin; Yu, Hong

2008-01-01

Objective To examine the feasibility of using blood-derived smooth muscle cells (BD-SMCs) as a target for to deliver therapeutic proteins. Materials and Methods Mononuclear cells (MNC) were isolated from peripheral blood. The outgrowth colonies from MNC culture were differentiated into BD-SMCs in media containing platelet-derived growth factor BB. Phenotypic characterization of BD-SMCs was assessed by immunocytochemistry. Cell proliferation, gene transfer efficiency with a retroviral vector, apoptosis, and the biological activity of the transduced gene product from the BD-SMCs were evaluated in vitro and in vivo in comparison with vascular derived SMC (VSMCs). Results BD-SMCs stained positive for SMC markers. No significant difference was observed between BD-SMCs and VSMCs in cell proliferation, migration, adhesiveness, and gene transfer efficiency. After BD-SMCs were transduced with a retroviral vector carrying the secreted alkaline phosphatase gene (SEAP), 174 ± 50 μg biologically active SEAP was produced per 106 cells over 24 hrs. After injecting 5×106 cells expressing SEAP intravenously into rabbits, SEAP concentration increased significantly in the circulation from 0.14 ± 0.04 μg/ml to 2.34 ± 0.16 μg/ml 3 days after cell injection (P<0.01, n=3). Circulating levels of SEAP decreased to 1.76 μg /ml one week later and remained at this level up to 8 weeks, then declined to pre-cell injection level at 12 weeks. VSMC in vivo gene expression data were equivalent. Conclusion BD-SMCs have similar characteristics to mature VSMCs, and can be used as a novel target for gene transfer to deliver a therapeutic protein. Clinical relevance Cell-based therapy strategies offer the potential to correct a wide spectrum of inherited and acquired human diseases. Translation to a clinical trial will require a detailed pre-clinical study to understand the characteristics of the isolated cells. BD-SMC are practical and effective targets for ex vivo genetic engineering. They are obtained with ease by phlebotomy, eliminating the need for surgical tissue explantation. This study tested the suitability of BD-SMC in vivo as a target for gene therapy. The outcome of the study has direct application in progenitor cell-based therapy. PMID:18241767

New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

DTIC Science & Technology

2014-07-01

mice injected with saline vehicle for 4 weeks (control no treatment=C-NT, n=5), b) pilocarpine-treated SpH mice that developed status epilepticus ...injected with saline ( status epilepticus no treatment=SE–NT, n=5), c) control SpH mice injected with levetiracetam (see below) (control treated=C-T, n...4), and d) pilocarpine-treated SpH mice that suffered status epilepticus and were treated subsequently with levetiracetam intraperitoneally (see

Changes in morphology and optical properties of sclera and choroidal layers due to hyperosmotic agent.

PubMed

Zaman, Raiyan T; Rajaram, Narasimhan; Nichols, Brandon S; Rylander, Henry G; Wang, Tianyi; Tunnell, James W; Welch, Ashley J

2011-07-01

Light scattering in the normally white sclera prevents diagnostic imaging or delivery of a focused laser beam to a target in the underlying choroid layer. In this study, we examine optical clearing of the sclera and changes in blood flow resulting from the application of glycerol to the sclera of rabbits. Recovery dynamics are monitored after the application of saline. The speed of clearing for injection delivery is compared to the direct application of glycerol through an incision in the conjunctiva. Although, the same volume of glycerol was applied, the sclera cleared much faster (5 to 10 s) with the topical application of glycerol compared to the injection method (3 min). In addition, the direct topical application of glycerol spreads over a larger area in the sclera than the latter method. A diffuse optical spectroscopy system provided spectral analysis of the remitted light every two minutes during clearing and rehydration. Comparison of measurements to those obtained from phantoms with various absorption and scattering properties provided estimates of the absorption coefficient and reduced scattering coefficient of rabbit eye tissue.

Differential experiences of Mexican policing by people who inject drugs residing in Tijuana and San Diego

PubMed Central

Wood, Emily F.; Werb, Dan; Beletsky, Leo; Rangel, Gudelia; Mota, Jazmine Cuevas; Garfein, Richard S.; Strathdee, Steffanie A.; Wagner, Karla D.

2017-01-01

Background Research among people who inject drugs (PWIDs) in the USA and Mexico has identified a range of adverse health impacts associated with policing of PWIDs. We employed a mixed methods design to investigate how PWIDs from San Diego and Mexico experienced policing in Tijuana, and how these interactions affect PWIDs behavior, stratifying by country of origin. Methods In 2012–2014, 575 PWIDs in San Diego, 102 of whom had used drugs in Mexico in the past six months, were enrolled in the STAHR-II study, with qualitative interviews conducted with a subsample of 20 who had recently injected drugs in Mexico. During this period, 735 PWIDs in Tijuana were also enrolled in the El Cuete-IV study, with qualitative interviews conducted with a subsample of 20 recently stopped by police. We calculated descriptive statistics for quantitative variables and conducted thematic analysis of qualitative transcripts. Integration of these data involved comparing frequencies across cohorts and using qualitative themes to explain and explore findings. Results Sixty-one percent of San Diego-based participants had been recently stopped by law enforcement officers (LEOs) in Mexico; 53% reported it was somewhat or very likely that they would be arrested while in Mexico because they look like a drug user. Ninety percent of Tijuana-based participants had been recently stopped by LEOs; 84% reported it was somewhat or very likely they could get arrested because they look like a drug user. Participants in both cohorts described bribery and targeting by LEOs in Mexico. However, most San Diego-based participants described compliance with bribery as a safeguard against arrest and detention, with mistreatment being rare. Tijuana-based participants described being routinely targeted by LEOs, were frequently detained, and reported instances of sexual and physical violence. Tijuana-based participants described modifying how, where, and with whom they injected drugs in response; and experienced feelings of stress, anxiety, and powerlessness. This was less common among San Diego-based participants, who mostly attempted to avoid contact with LEOs in Mexico while engaging in risky injection behavior. Conclusion Experiences of discrimination and stigma were reported by a larger proportion of PWIDs living in Mexico, suggesting that they may be subject to greater health harms related to policing practices compared with those residing in the USA. Our findings reinforce the importance of efforts to curb abuse and align policing practices with public health goals in both the US and Mexico. PMID:28111221

Targeted Near-Infrared Fluorescence Imaging of Atherosclerosis: Clinical and Intracoronary Evaluation of Indocyanine Green.

PubMed

Verjans, Johan W; Osborn, Eric A; Ughi, Giovanni J; Calfon Press, Marcella A; Hamidi, Ehsan; Antoniadis, Antonios P; Papafaklis, Michail I; Conrad, Mark F; Libby, Peter; Stone, Peter H; Cambria, Richard P; Tearney, Guillermo J; Jaffer, Farouc A

2016-09-01

This study sought to determine whether indocyanine green (ICG)-enhanced near-infrared fluorescence (NIRF) imaging can illuminate high-risk histologic plaque features of human carotid atherosclerosis, and in coronary atheroma of living swine, using intravascular NIRF-optical coherence tomography (OCT) imaging. New translatable imaging approaches are needed to identify high-risk biological signatures of atheroma. ICG is a U.S. Food and Drug Administration-approved NIRF imaging agent that experimentally targets plaque macrophages and lipid in areas of enhanced endothelial permeability. However, it is unknown whether ICG can target atheroma in patients. Eight patients were enrolled in the BRIGHT-CEA (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque) trial. Five patients were injected intravenously with ICG 99 ± 25 min before clinically indicated carotid endarterectomy. Three saline-injected endarterectomy patients served as control subjects. Excised plaques underwent analysis by intravascular NIRF-OCT, reflectance imaging, microscopy, and histopathology. Next, following ICG intravenous injection, in vivo intracoronary NIRF-OCT and intravascular ultrasound imaged 3 atheroma-bearing coronary arteries of a diabetic, cholesterol-fed swine. ICG was well tolerated; no adverse clinical events occurred up to 30 days post-injection. Multimodal NIRF imaging including intravascular NIRF-OCT revealed that ICG accumulated in all endarterectomy specimens. Plaques from saline-injected control patients exhibited minimal NIRF signal. In the swine experiment, intracoronary NIRF-OCT identified ICG uptake in all intravascular ultrasound-identified plaques in vivo. On detailed microscopic evaluation, ICG localized to plaque areas exhibiting impaired endothelial integrity, including disrupted fibrous caps, and within areas of neovascularization. Within human plaque areas of endothelial abnormality, ICG was spatially related to localized zones of plaque macrophages and lipid, and, notably, intraplaque hemorrhage. This study demonstrates that ICG targets human plaques exhibiting endothelial abnormalities and provides new insights into its targeting mechanisms in clinical and experimental atheroma. Intracoronary NIRF-OCT of ICG may offer a novel, clinically translatable approach to image pathobiological aspects of coronary atherosclerosis. (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque [BRIGHT-CEA]; NCT01873716). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Bundling occupational safety with harm reduction information as a feasible method for improving police receptiveness to syringe access programs: evidence from three U.S. cities

PubMed Central

Davis, Corey S; Beletsky, Leo

2009-01-01

Introduction In light of overwhelming evidence that access to sterile injection equipment reduces incidence of injection-attributable bloodborne disease without encouraging drug use, many localities have authorized sterile syringe access programs (SAPs), including syringe exchange and pharmacy-based initiatives. Even where such interventions are clearly legal, many law enforcement officers are unaware of the public health benefits and legal status of these programs and may continue to treat the possession of injection equipment as illegal and program participation as a marker of illegal behavior. Law enforcement practice can impede SAP utilization and may increase the risk of needlestick injury (NSI) among law enforcement personnel. Many SAPs conduct little or no outreach to law enforcement, in part because they perceive law enforcement actors as unreceptive to health-promotion programs targeting drug users. Case description We report on a brief training intervention for law enforcement personnel designed to increase officer knowledge of and positive attitudes towards SAPs by bundling content that addresses officer concerns about infectious disease and occupational safety with information about the legality and public health benefits of these programs. Pilot trainings using this bundled curriculum were conducted with approximately 600 officers in three US cities. Discussion and evaluation Law enforcement officers were generally receptive to receiving information about SAPs through the bundled curriculum. The trainings led to better communication and collaboration between SAP and law enforcement personnel, providing a valuable platform for better harmonization of law enforcement and public health activities targeting injection drug users. Conclusion The experience in these three cities suggests that a harm reduction training curriculum that bundles strategies for increasing officer occupational safety with information about the legality and public health benefits of SAPs can be well received by law enforcement personnel and can lead to better communication and collaboration between law enforcement and harm reduction actors. Further study is indicated to assess whether such a bundled curriculum is effective in changing officer attitudes and beliefs and reducing health risks to officers and injection drug users, as well as broader benefits to the community at large. PMID:19602236

Three-dimensional rotational angiography fused with multimodal imaging modalities for targeted endomyocardial injections in the ischaemic heart.

PubMed

Dauwe, Dieter Frans; Nuyens, Dieter; De Buck, Stijn; Claus, Piet; Gheysens, Olivier; Koole, Michel; Coudyzer, Walter; Vanden Driessche, Nina; Janssens, Laurens; Ector, Joris; Dymarkowski, Steven; Bogaert, Jan; Heidbuchel, Hein; Janssens, Stefan

2014-08-01

Biological therapies for ischaemic heart disease require efficient, safe, and affordable intramyocardial delivery. Integration of multiple imaging modalities within the fluoroscopy framework can provide valuable information to guide these procedures. We compared an anatomo-electric method (LARCA) with a non-fluoroscopic electromechanical mapping system (NOGA(®)). LARCA integrates selective three-dimensional-rotational angiograms with biplane fluoroscopy. To identify the infarct region, we studied LARCA-fusion with pre-procedural magnetic resonance imaging (MRI), dedicated CT, or (18)F-FDG-PET/CT. We induced myocardial infarction in 20 pigs by 90-min LAD occlusion. Six weeks later, we compared peri-infarct delivery accuracy of coloured fluospheres using sequential NOGA(®)- and LARCA-MRI-guided vs. LARCA-CT- and LARCA-(18)F-FDG-PET/CT-guided intramyocardial injections. MRI after 6 weeks revealed significant left ventricular (LV) functional impairment and remodelling (LVEF 31 ± 3%, LVEDV 178 ± 15 mL, infarct size 17 ± 2% LV mass). During NOGA(®)-procedures, three of five animals required DC-shock for major ventricular arrhythmias vs. one of ten during LARCA-procedures. Online procedure time was shorter for LARCA than NOGA(®) (77 ± 6 vs. 130 ± 3 min, P < 0.0001). Absolute distance of injection spots to the infarct border was similar for LARCA-MRI (4.8 ± 0.5 mm) and NOGA(®) (5.4 ± 0.5 mm). LARCA-CT-integration allowed closer approximation of the targeted border zone than LARCA-PET (4.0 ± 0.5 mm vs. 6.2 ± 0.6 mm, P < 0.05). Three-dimensional -rotational angiography fused with multimodal imaging offers a new, cost-effective, and safe strategy to guide intramyocardial injections. Endoventricular procedure times and arrhythmias compare favourably to NOGA(®), without compromising injection accuracy. LARCA-based fusion imaging is a promising enabling technology for cardiac biological therapies. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Identification of Staphylococcus aureus infection by aptamers directly radiolabeled with technetium-99m.

PubMed

dos Santos, Sara Roberta; Rodrigues Corrêa, Cristiane; Branco de Barros, André Luís; Serakides, Rogéria; Fernandes, Simone Odília; Cardoso, Valbert Nascimento; de Andrade, Antero Silva Ribeiro

2015-03-01

Aptamers are oligonucleotides that have high affinity and specificity for their molecular targets which are emerging as a new class of molecules for radiopharmaceuticals development. In this study, aptamers selected to Staphylococcus aureus were evaluated for bacterial infection identification. Anti S. aureus aptamers were labeled with (99m)Tc by the direct method. The radiolabel yield and complex stability were assessed by thin-layer chromatography (TLC). Three groups of Swiss mice containing 6 animals each were used. The first group was infected intramuscularly in the right thigh with S. aureus. The second group was infected in the same way with C. albicans and the third group was injected with zymosan to induce aseptic inflammation. After 24 h, radiolabeled aptamers (22.2 MBq) were injected by the tail vein. The mice were euthanized 4 h post injection and tissue sample activities measured in a gamma counter. The (99m)Tc labeled aptamers were stable in saline, plasma and cystein excess. Radiolabeled aptamers showed increased uptake in the kidneys for all groups indicating a main renal excretion, which is consistent with the hydrophilic nature and small size of aptamers. The radiopharmaceutical showed rapid blood clearance indicated by a reduced dose (% ID/g) in the blood. The biodistribution showed that aptamers were able to identify the infection foci caused by S. aureus displaying a target/non-target ratio of 4.0±0.5. This ratio for mice infected with C. albicans was 2.0±0.4 while for mice with aseptic inflammation was 1.2±0.2. Histology confirmed the presence of infection in groups 1 and 2, and inflammation in group 3. The biodistibution study demonstrated a statistically higher uptake in the S. aureus foci relative to inflammation and C. albicans infected areas. These results highlight the potential of aptamers labeled directly with (99m)Tc for bacterial infection diagnosis by scintigraphy. Copyright © 2014 Elsevier Inc. All rights reserved.

Specific α4β2 Nicotinic Acetylcholine Receptor Binding of [F-18]Nifene in the Rhesus Monkey

PubMed Central

Hillmer, A.T.; Wooten, D.W.; Moirano, J.; Slesarev, M.; Barnhart, T.E.; Engle, J.W.; Nickles, R.J.; Murali, D.; Schneider, M.; Mukherjee, J.; Christian, B.T.

2013-01-01

Objective [F-18]Nifene is a PET radioligand developed to image α4β2* nicotinic acetylcholine receptors (nAChR) in the brain. This work assesses the in vivo binding and imaging characteristics of [F-18]nifene in rhesus monkeys for the development of PET experiments examining nAChR binding. Methods Dynamic PET imaging experiments with [F-18]nifene were acquired in 4 anesthetized macaca mulatta (rhesus) monkeys using a microPET P4 scanner. Data acquisition was initiated with a bolus injection of 109 ± 17 MBq [F-18]nifene and the time course of the radioligand in the brain was measured for up to 120 minutes. For two experiments, a displacement dose of (−)nicotine (0.03 mg/kg, i.v.) was given 45–60 minutes post injection and followed 30 minutes later with a second [F-18]nifene injection to measure radioligand nondisplaceable uptake. Time activity curves were extracted in the regions of the antereoventral thalamus (AVT), lateral geniculate nucleus region (LGN), frontal cortex, and the cerebellum (CB). Results The highest levels of [F-18]nifene uptake were observed in the AVT and LGN. Target-to-CB ratios reached maximum values of 3.3 ± 0.4 in the AVT and 3.2 ± 0.3 in the LG 30–45 minutes post-injection. Significant binding of [F-18]nifene was observed in the subiculum, insula cortex, temporal cortex, cingulate gyrus, frontal cortex, striatum, and midbrain areas. The (−)nicotine displaced bound [F-18]nifene to near background levels within 15 minutes post-drug injection. No discernable displacement was observed in the CB, suggesting its potential as a reference region. Logan graphical estimates using the CB as a reference region yielded binding potentials (BPND) of 1.6 ± 0.1 in the AVT, and 1.3 ± 0.1 in the LGN. The post-nicotine injection displayed uniform nondisplaceable uptake of [F-18]nifene throughout gray and white brain matter. Conclusions [F-18]Nifene exhibits rapid equilibration and a moderately high target to background binding profile in the α4β2* nAChR rich regions of the brain, thus providing favorable imaging characteristics as a PET radiotracer for nAChR assay. PMID:21674627

Can We Estimate Injected Carbon Dioxide Prior to the Repeat Survey in 4D Seismic Monitoring Scheme?

NASA Astrophysics Data System (ADS)

Sakai, A.

2005-12-01

To mitigate global climate change, the geologic sequestration by injecting carbon dioxide in the aquifer and others is one of the most promising scenarios. Monitoring is required to verify the long-term safe storage of carbon dioxide in the subsurface. As evidenced in the oil industry, monitoring by time-lapse 3D seismic survey is the most effective to spatially detect fluid movements and change of pore pressure. We have conducted 3D seismic survey onshore Japan surrounding RITE/METI Iwanohara carbon dioxide injection test site. Target aquifer zone is at 1100m deep in the Pleistocene layer with 60m thick and most permeable zone is approx. 12m thick. Baseline 3D seismic survey was conducted in July-August 2003 and a monitor 3D seismic survey was in July-August 2005 by vibrating source with 10-120Hz sweep frequency band. Prior to the monitor survey, we evaluated seismic data with integrating wireline logging data. As target carbon dioxide injection layer is thin, high-resolution seismic data is required to estimate potential spreading of injected carbon dioxide. To increase seismic resolution, spectrally enhancing method was in use. The procedure is smoothing number of seismic spectral amplitude, computing well log spectrum, and constructing matching filter between seismic and well spectrum. Then it was applied to the whole seismic traces after evaluating test traces. Synthetic seismograms from logging data were computed with extracting optimal wavelets. Fitting between spectrally enhanced seismic traces and synthetic seismograms was excellent even for deviated monitor wells. Acoustic impedance was estimated by inversion of these 3D seismic traces. In analyzing logging data of sonic, density, CMR, and others, the elastic wave velocity was reconstructed by rock physics approach after estimating compositions. Based on models, velocity changes by carbon dioxide injection was evaluated. The correlation of acoustic impedance with porosity and logarithmic permeability was good and relying on this relation and geological constraints with inversion techniques, porosity and permeability was estimated in 3D volume. If the carbon dioxide movement was solely controlled by permeability, estimated permeability volume might predict the time-lapse seismic data prior to a repeat survey. We compare the estimate with the actual 4D changes and discuss related variations.

Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer.

PubMed

Semkina, Alevtina S; Abakumov, Maxim A; Skorikov, Alexander S; Abakumova, Tatiana O; Melnikov, Pavel A; Grinenko, Nadejda F; Cherepanov, Sergey A; Vishnevskiy, Daniil A; Naumenko, Victor A; Ionova, Klavdiya P; Majouga, Alexander G; Chekhonin, Vladimir P

2018-05-03

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics. Copyright © 2018. Published by Elsevier Inc.

Evaluation of the Possible Utilization of 68Ga-DOTATOC in Diagnosis of Adenocarcinoma Breast Cancer.

PubMed

Zolghadri, Samaneh; Naderi, Mojdeh; Yousefnia, Hassan; Alirezapour, Behrouz; Beiki, Davood

2018-01-01

Studies have indicated advantageous properties of [DOTA-DPhe 1 , Tyr 3 ] octreotide (DOTATOC) in tumor models and labeling with gallium. Breast cancer is the second leading cause of cancer mortality in women, and most of these cancers are often an adenocarcinoma. Due to the importance of target to non-target ratios in the efficacy of diagnosis, the pharmacokinetic of 68 Ga-DOTATOC in an adenocarcinoma breast cancer animal model was studied in this research, and the optimized time for imaging was determined. 68 Ga was obtained from 68 Ge/ 68 Ga generator. The complex was prepared at optimized conditions. Radiochemical purity of the complex was checked using both HPLC and ITLC methods. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer. Also, PET/CT imaging was performed up to 120 min post injection. The complex was produced with radiochemical purity of greater than 98% and specific activity of about 40 GBq/mM at optimized conditions. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer indicated fast blood clearance and significant uptake in the tumor. Significant tumor: blood and tumor:muscle uptake ratios were observed even at early times post-injection. PET/CT images were also confirmed the considerable accumulation of the tracer in the tumor. Generally, the results proved the possible application of the radiolabelled complex for the detection of the adenocarcinoma breast cancer and according to the pharmacokenitic data, the suitable time for imaging was determined as at least 30 min after injection.

Broad protection against influenza infection by vectored immunoprophylaxis in mice

PubMed Central

Balazs, Alejandro B.; Bloom, Jesse D.; Hong, Christin M.; Rao, Dinesh S.; Baltimore, David

2014-01-01

Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines. PMID:23728362

Ultrasound-guided percutaneous injection of methylene blue to identify nerve pathology and guide surgery.

PubMed

Osorio, Joseph A; Breshears, Jonathan D; Arnaout, Omar; Simon, Neil G; Hastings-Robinson, Ashley M; Aleshi, Pedram; Kliot, Michel

2015-09-01

OBJECT The objective of this study was to provide a technique that could be used in the preoperative period to facilitate the surgical exploration of peripheral nerve pathology. METHODS The authors describe a technique in which 1) ultrasonography is used in the immediate preoperative period to identify target peripheral nerves, 2) an ultrasound-guided needle electrode is used to stimulate peripheral nerves to confirm their position, and then 3) a methylene blue (MB) injection is performed to mark the peripheral nerve pathology to facilitate surgical exploration. RESULTS A cohort of 13 patients with varying indications for peripheral nerve surgery is presented in which ultrasound guidance, stimulation, and MB were used to localize and create a road map for surgeries. CONCLUSIONS Preoperative ultrasound-guided MB administration is a promising technique that peripheral nerve surgeons could use to plan and execute surgery.

Narrowing the scope of failure prediction using targeted fault load injection

NASA Astrophysics Data System (ADS)

Jordan, Paul L.; Peterson, Gilbert L.; Lin, Alan C.; Mendenhall, Michael J.; Sellers, Andrew J.

2018-05-01

As society becomes more dependent upon computer systems to perform increasingly critical tasks, ensuring that those systems do not fail becomes increasingly important. Many organizations depend heavily on desktop computers for day-to-day operations. Unfortunately, the software that runs on these computers is written by humans and, as such, is still subject to human error and consequent failure. A natural solution is to use statistical machine learning to predict failure. However, since failure is still a relatively rare event, obtaining labelled training data to train these models is not a trivial task. This work presents new simulated fault-inducing loads that extend the focus of traditional fault injection techniques to predict failure in the Microsoft enterprise authentication service and Apache web server. These new fault loads were successful in creating failure conditions that were identifiable using statistical learning methods, with fewer irrelevant faults being created.

Quantitative Estimation of Seismic Velocity Changes Using Time-Lapse Seismic Data and Elastic-Wave Sensitivity Approach

NASA Astrophysics Data System (ADS)

Denli, H.; Huang, L.

2008-12-01

Quantitative monitoring of reservoir property changes is essential for safe geologic carbon sequestration. Time-lapse seismic surveys have the potential to effectively monitor fluid migration in the reservoir that causes geophysical property changes such as density, and P- and S-wave velocities. We introduce a novel method for quantitative estimation of seismic velocity changes using time-lapse seismic data. The method employs elastic sensitivity wavefields, which are the derivatives of elastic wavefield with respect to density, P- and S-wave velocities of a target region. We derive the elastic sensitivity equations from analytical differentiations of the elastic-wave equations with respect to seismic-wave velocities. The sensitivity equations are coupled with the wave equations in a way that elastic waves arriving in a target reservoir behave as a secondary source to sensitivity fields. We use a staggered-grid finite-difference scheme with perfectly-matched layers absorbing boundary conditions to simultaneously solve the elastic-wave equations and the elastic sensitivity equations. By elastic-wave sensitivities, a linear relationship between relative seismic velocity changes in the reservoir and time-lapse seismic data at receiver locations can be derived, which leads to an over-determined system of equations. We solve this system of equations using a least- square method for each receiver to obtain P- and S-wave velocity changes. We validate the method using both surface and VSP synthetic time-lapse seismic data for a multi-layered model and the elastic Marmousi model. Then we apply it to the time-lapse field VSP data acquired at the Aneth oil field in Utah. A total of 10.5K tons of CO2 was injected into the oil reservoir between the two VSP surveys for enhanced oil recovery. The synthetic and field data studies show that our new method can quantitatively estimate changes in seismic velocities within a reservoir due to CO2 injection/migration.

Evaluation of the impact of matrix effect on quantification of pesticides in foods by gas chromatography-mass spectrometry using isotope-labeled internal standards.

PubMed

Yarita, Takashi; Aoyagi, Yoshie; Otake, Takamitsu

2015-05-29

The impact of the matrix effect in GC-MS quantification of pesticides in food using the corresponding isotope-labeled internal standards was evaluated. A spike-and-recovery study of nine target pesticides was first conducted using paste samples of corn, green soybean, carrot, and pumpkin. The observed analytical values using isotope-labeled internal standards were more accurate for most target pesticides than that obtained using the external calibration method, but were still biased from the spiked concentrations when a matrix-free calibration solution was used for calibration. The respective calibration curves for each target pesticide were also prepared using matrix-free calibration solutions and matrix-matched calibration solutions with blank soybean extract. The intensity ratio of the peaks of most target pesticides to that of the corresponding isotope-labeled internal standards was influenced by the presence of the matrix in the calibration solution; therefore, the observed slope varied. The ratio was also influenced by the type of injection method (splitless or on-column). These results indicated that matrix-matching of the calibration solution is required for very accurate quantification, even if isotope-labeled internal standards were used for calibration. Copyright © 2015 Elsevier B.V. All rights reserved.

Contrast imaging in mouse embryos using high-frequency ultrasound.

PubMed

Denbeigh, Janet M; Nixon, Brian A; Puri, Mira C; Foster, F Stuart

2015-03-04

Ultrasound contrast-enhanced imaging can convey essential quantitative information regarding tissue vascularity and perfusion and, in targeted applications, facilitate the detection and measure of vascular biomarkers at the molecular level. Within the mouse embryo, this noninvasive technique may be used to uncover basic mechanisms underlying vascular development in the early mouse circulatory system and in genetic models of cardiovascular disease. The mouse embryo also presents as an excellent model for studying the adhesion of microbubbles to angiogenic targets (including vascular endothelial growth factor receptor 2 (VEGFR2) or αvβ3) and for assessing the quantitative nature of molecular ultrasound. We therefore developed a method to introduce ultrasound contrast agents into the vasculature of living, isolated embryos. This allows freedom in terms of injection control and positioning, reproducibility of the imaging plane without obstruction and motion, and simplified image analysis and quantification. Late gestational stage (embryonic day (E)16.6 and E17.5) murine embryos were isolated from the uterus, gently exteriorized from the yolk sac and microbubble contrast agents were injected into veins accessible on the chorionic surface of the placental disc. Nonlinear contrast ultrasound imaging was then employed to collect a number of basic perfusion parameters (peak enhancement, wash-in rate and time to peak) and quantify targeted microbubble binding in an endoglin mouse model. We show the successful circulation of microbubbles within living embryos and the utility of this approach in characterizing embryonic vasculature and microbubble behavior.

Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue

PubMed Central

Joshi, Shailendra; Singh-Moon, Rajinder P.; Wang, Mei; Chaudhuri, Durba B.; Holcomb, Mark; Straubinger, Ninfa L.; Bruce, Jeffrey N.; Bigio, Irving J.; Straubinger, Robert M.

2014-01-01

Object Transient cerebral hypoperfusion (TCH) has empirically been used to assist intraarterial (IA) drug delivery to brain tumors. Transient (< 3 min) reduction of cerebral blood flow (CBF) occurs during many neuro- and cardiovascular interventions and has recently been used to better target IA drugs to brain tumors. In the present experiments, we assessed whether the effectiveness of IA delivery of cationic liposomes could be improved by TCH. Methods Cationic liposomes composed of 1:1 DOTAP:PC (dioleoyl-trimethylammonium-propane:phosphatidylcholine) were administered to three groups of Sprague Dawley rats. In the first group, we tested the effect of blood flow reduction on IA delivery of cationic liposomes. In the second group, we compared TCH-assisted IA liposomal delivery vs. intravenous (IV) administration of the same dose. In the third group, we assessed retention of cationic liposomes in brain four hours after TCH assisted delivery. The liposomes contained a near infrared dye, DilC18(7), whose concentration could be measured in vivo by diffuse reflectance spectroscopy. Results IA injections of cationic liposomes during TCH increased their delivery approximately four-fold compared to injections during normal blood flow. Optical pharmacokinetic measurements revealed that relative to IV injections, IA injection of cationic liposomes during TCH produced tissue concentrations that were 100-fold greater. The cationic liposomes were retained in the brain tissue four hours after a single IA injection. There was no gross impairment of neurological functions in surviving animals. Conclusions Transient reduction in CBF significantly increased IA delivery of cationic liposomes in the brain. High concentrations of liposomes could be delivered to brain tissue after IA injections with concurrent TCH while none could be detected after IV injection. IA-TCH injections were well tolerated and cationic liposomes were retained for at least 4 hours after IA administration. These results should encourage development of cationic liposomal formulations of chemotherapeutic drugs and their IA delivery during TCH. PMID:24664370

Reservoir response to thermal and high-pressure well stimulation efforts at Raft River, Idaho

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plummer, Mitchell; Bradford, Jacob; Moore, Joseph

An injection stimulation test begun at the Raft River geothermal reservoir in June, 2013 has produced a wealth of data describing well and reservoir response via high-resolution temperature logging and distributed temperature sensing, seismic monitoring, periodic borehole televiewer logging, periodic stepped flow rate tests and tracer injections before and after stimulation efforts. One of the primary measures of response to the stimulation is the relationship between fluid pressure and flow rate, short-term during forced flow rate changes and the long-term change in injectivity. In this paper we examine that hydraulic response using standard pumping test analysis methods, largely because pressuremore » response to the stimulation was not detected, or measurable, in other wells. Analysis of stepped rate flow tests supports the inference from other data that a large fracture, with a radial extent of one to several meters, intersects the well in the target reservoir, suggests that the flow regime is radial to a distance of only several meters and demonstrates that the pressure build-up cone reaches an effective constant head at that distance. The well’s longer term hydraulic response demonstrated continually increasing injectivity but at a dramatically faster rate later from ~2 years out and continuing to the present. The net change in injectivity is significantly greater than observed in other longterm injectivity monitoring studies, with an approximately 150–fold increase occurring over ~2.5 years. While gradually increasing injectivity is a likely consequence of slow migration of a cooling front, and consequent dilation of fractures, the steady, ongoing, rate of increase is contrary to what would be expected in a radial or linear flow regime, where the cooling front would slow with time. As a result, occasional step-like changes in injectivity, immediately following high-flow rate tests suggest that hydro shearing during high-pressure testing altered the near-well permeability structure.« less

Resveratrol Targets AKT and p53 in Glioblastoma and Glioblastoma Stem-like Cells to Suppress Growth and Infiltration

PubMed Central

Clark, Paul A.; Bhattacharya, Saswati; Elmayan, Ardem; Darjatmoko, Soesiawati R.; Thuro, Bradley A.; Yan, Michael B.; van Ginkel, Paul R.; Polans, Arthur S.; Kuo, John S.

2016-01-01

Object Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than two years with current treatment. GBM exhibits extensive intra-tumor and inter-patient heterogeneity, suggesting that successful therapies should exert broad anti-cancer activities. Therefore, the natural non-toxic pleiotropic agent, resveratrol, was studied for anti-tumorigenic effects against GBM. Methods Resveratrol’s effects on cell proliferation, sphere-forming ability, and invasion were tested using multiple patient-derived GBM stem-like cell (GSC) lines and established U87 glioma cells, and changes in oncogenic AKT and tumor suppressive p53 were analyzed. Resveratrol was also tested in vivo against U87 glioma flank xenografts using multiple delivery methods, including direct tumor injection. Finally, resveratrol was delivered directly to brain tissue to determine toxicity and achievable drug concentrations in the brain parenchyma. Results Resveratrol significantly inhibited proliferation in U87 glioma and multiple patient-derived GSC lines, demonstrating similar inhibitory concentrations across these phenotypically heterogeneous lines. Resveratrol also inhibited the sphere-forming ability of GSCs, suggesting anti-stem cell effects. Additionally, resveratrol blocked U87 glioma and GSC invasion in an in vitro Matrigel transwell assay at doses similar to those mediating anti-proliferative effects. In U87 glioma cells and GSCs, resveratrol reduced AKT phosphorylation and induced p53 expression and activation that led to transcription of downstream p53 target genes. Resveratrol administration via oral gavage or ad libitum in the water supply significantly suppressed GBM xenograft growth; intra-tumor or peri-tumor resveratrol injection further suppressed growth and approximating tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared to intravenous delivery, and with no apparent toxicity. Conclusions Resveratrol potently inhibited GBM and GBM stem-like cell growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed glioblastoma growth in vivo. The ability of resveratrol to modulate AKT and p53, as well as reportedly many other anti-tumorigenic pathways, is attractive for therapy against a genetically heterogeneous tumor such as GBM. Although resveratrol exhibits low bioavailability when administered orally or intravenously, novel delivery methods such as direct injection (i.e. convection enhanced delivery) could potentially be used to achieve and maintain therapeutic doses in brain. Resveratrol’s non-toxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies. PMID:27419830

Intracranial hypotension headache caused by a massive cerebrospinal fluid leak successfully treated with a targeted c2 epidural blood patch: a case report.

PubMed

Sykes, Kenneth T; Yi, Xiaobin

2013-01-01

Cervical epidural steroid injections, administered either interlaminarly or transforaminally, are common injection therapies used in many interventional pain management practices to treat cervicalgia or cervicobrachial pain secondary to spondylosis or intervertebral disc displacement of the cervical spine. Among the risks associated with these procedures are the risk for inadvertent dural puncture and the development of positional headache from intracranial hypotension. We report the case of a 31-year-old woman with a history of migraine and cervicalgia from cervical spine spondylosis and cervical disc degenerative disease that developed an intractable orthostatic headache accompanied by nausea and vomiting after a therapeutic high cervical intralaminar epidural steroid injection was administered directly to the C1-C2 spinal level. Although the initial magnetic resonance imaging of the brain was unremarkable, a computed tomography myelogram study revealed a massive cerebrospinal fluid (CSF) leak from the cervical spine.  Repeated cervical epidural blood patches using a catheter targeted to the high cervical spine (C2) to inject 15 mL of autologous blood was required to totally alleviate her symptoms after she failed conservative therapy. Determining the optimal location or approach to administer an epidural blood patch can be a challenge depending on the location of the CSF leak. Our case demonstrates that targeted cervical epidural blood patch placement using an easily manipulated catheter under fluoroscopic guidance is a safe and effective approach to treat a massive CSF leak in the high cervical spine region caused by prior therapeutic cervical spine epidural steroid injection.

Multiresidue analysis of acidic and polar organic contaminants in water samples by stir-bar sorptive extraction-liquid desorption-gas chromatography-mass spectrometry.

PubMed

Quintana, José Benito; Rodil, Rosario; Muniategui-Lorenzo, Soledad; López-Mahía, Purificación; Prada-Rodríguez, Darío

2007-12-07

The feasibility of stir-bar sorptive extraction (SBSE) followed by liquid desorption in combination with large volume injection (LVI)-in port silylation and gas chromatography-mass spectrometry (GC-MS) for the simultaneous determination of a broad range of 46 acidic and polar organic pollutants in water samples has been evaluated. The target analytes included phenols (nitrophenols, chlorophenols, bromophenols and alkylphenols), acidic herbicides (phenoxy acids and dicamba) and several pharmaceuticals. Experimental variables affecting derivatisation yield and peak shape as a function of different experimental PTV parameters [initial injection time, pressure and temperature and the ratio solvent volume/N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA) volume] were first optimised by an experimental design approach. Subsequently, SBSE conditions, such as pH, ionic strength, agitation speed and extraction time were investigated. After optimisation, the method failed only for the extraction of most polar phenols and some pharmaceuticals, being suitable for the determination of 37 (out of 46) pollutants, with detection limits for these analytes ranging between 1 and 800 ng/L and being lower than 25 ng/L in most cases. Finally, the developed method was validated and applied to the determination of target analytes in various aqueous environmental matrices, including ground, river and wastewater. Acceptable accuracy (70-130%) and precision values (<20%) were obtained for most analytes independently of the matrix, with the exception of some alkylphenols, where an isotopically labelled internal standard would be required in order to correct for matrix effects. Among the drawbacks of the method, carryover was identified as the main problem even though the Twisters were cleaned repeatedly.

EBCO Technologies TR Cyclotrons, Dynamics, Equipment, and Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, R.R.; Univ British Columbia; Erdman, K. L.

2003-08-26

The Ebco Technologies TR cyclotrons have a common parent in the 500 MeV negative ion cyclotron at TRIUMF in Vancouver. As such, the TR cyclotrons have features that can be adapted for specific application. The cyclotron design is modularized into ion source and injection system, central region and then extraction. The cyclotron ion source is configured for cyclotron beam currents ranging from 50 microAmps to 2 milliAmps. The injection line can be operated in either continuous (CW) or in pulsed mode. The center region of the cyclotron is configured to match the ion source configuration. The extracted beams are directedmore » either to a local target station or to beam lines and thence to target stations. There has been development both in solid, liquid and gas targets. There has been development in radioisotope handling techniques, target material recovery and radiochemical synthesis.« less

Targeting the lymphatics using dendritic polymers (dendrimers).

PubMed

Kaminskas, Lisa M; Porter, Christopher J H

2011-09-10

Dendrimers are unique biomaterials that are constructed by the stepwise addition of layers (generations) of polymer around a central core. They can be constructed with a range of molecular weights and have a polyfunctional surface that facilitates the attachment of drugs and pharmacokinetic modifiers such PEG or targeting moieties. These properties have led to considerable interest in the development of dendrimers for a range of biomedical applications. After subcutaneous administration, larger dendrimers in particular (> 8 nm), preferentially drain from the injection site into the peripheral lymphatic capillaries and therefore have potential as lymphatic imaging agents for magnetic resonance and optical fluorescence lymphangiography and as vectors for drug-targeting to lymphatic sites of disease progression. In general, lymphatic targeting of dendrimers is enhanced by increasing size although ultimately larger constructs may be incompletely absorbed from the injection site. Increasing hydrophilicity and reducing surface charge enhances drainage from subcutaneous injection sites, but the reverse is true of uptake into lymph nodes where charge and hydrophobicity promote retention. Larger hydrophilic dendrimers are also capable of extravasation from the systemic circulation, absorption into the lymphatic system and recirculation into the blood. Lymphatic recirculation may therefore be a characteristic of PEGylated dendrimers with long systemic circulation times. Copyright © 2011 Elsevier B.V. All rights reserved.

Diagnostics and Identification of Injection Duration of Common Rail Diesel Injectors

NASA Astrophysics Data System (ADS)

Krogerus, Tomi R.; Huhtala, Kalevi J.

2018-02-01

In this paper, we study the diagnostics and identification of injection duration of common rail (CR) diesel pilot injectors of dual-fuel engines. In these pilot injectors, the injected volume is small and the repeatability of the injections and identification of the drifts of the injectors are important factors, which need to be taken into account in achieving good repeatability (shot-to-shot with every cylinder) and therefore a well-balanced engine and reduced overall wear. A diagnostics method based on analysis of CR pressure signal with experimental verification results is presented. Using the developed method, the relative duration of injection events can be identified. In the method, the pressure signal during the injection is first extracted after the control of each injection event. After that, the signal is normalized and filtered. Then a derivative of the filtered signal is calculated. Change in the derivative of the filtered signal larger than a predefined threshold indicates an injection event which can be detected and its relative duration can be identified. The efficacy of the proposed diagnostics method is presented with the experimental results, which show that the developed method detects drifts in injection duration and the magnitude of drift. According to the result, ≥ 10 μs change (2%, 500 μs) in injection time can be identified.

Immuno-biosensor for Detection of CD20-Positive Cells Using Surface Plasmon Resonance.

PubMed

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili; Fathi, Farzaneh; Ezzati Nazhad Dolatabadi, Jafar

2017-06-01

Purpose: Surface plasmon resonance (SPR) sensing confers a real-time assessment of molecular interactions between biomolecules and their ligands. This approach is highly sensitive and reproducible and could be employed to confirm the successful binding of drugs to cell surface targets. The specific affinity of monoclonal antibodies (MAb) for their target antigens is being utilized for development of immuno-sensors and therapeutic agents. CD20 is a surface protein of B lymphocytes which has been widely employed for immuno-targeting of B-cell related disorders. In the present study, binding ability of an anti-CD20 MAb to surface antigens of intact target cells was investigated by SPR technique. Methods: Two distinct strategies were used for immobilization of the anti-CD20 MAb onto gold (Au) chips. MUA (11-mercaptoundecanoic acid) and Staphylococcus aureus protein A (SpA) were the two systems used for this purpose. A suspension of CD20-positive Raji cells was injected in the analyte phase and the resulting interactions were analyzed and compared to those of MOLT-4 cell line as CD20-negative control. Results: Efficient binding of anti-CD20 MAb to the surface antigens of Raji cell line was confirmed by both immobilizing methods, whereas this MAb had not a noticeable affinity to the MOLT-4 cells. Conclusion: According to the outcomes, the investigated MAb had acceptable affinity and specificity to the target antigens on the cell surface and could be utilized for immuno-detection of CD20-positive intact cells by SPR method.

Immuno-biosensor for Detection of CD20-Positive Cells Using Surface Plasmon Resonance

PubMed Central

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili; Fathi, Farzaneh; Ezzati Nazhad Dolatabadi, Jafar

2017-01-01

Purpose: Surface plasmon resonance (SPR) sensing confers a real-time assessment of molecular interactions between biomolecules and their ligands. This approach is highly sensitive and reproducible and could be employed to confirm the successful binding of drugs to cell surface targets. The specific affinity of monoclonal antibodies (MAb) for their target antigens is being utilized for development of immuno-sensors and therapeutic agents. CD20 is a surface protein of B lymphocytes which has been widely employed for immuno-targeting of B-cell related disorders. In the present study, binding ability of an anti-CD20 MAb to surface antigens of intact target cells was investigated by SPR technique. Methods: Two distinct strategies were used for immobilization of the anti-CD20 MAb onto gold (Au) chips. MUA (11-mercaptoundecanoic acid) and Staphylococcus aureus protein A (SpA) were the two systems used for this purpose. A suspension of CD20-positive Raji cells was injected in the analyte phase and the resulting interactions were analyzed and compared to those of MOLT-4 cell line as CD20-negative control. Results: Efficient binding of anti-CD20 MAb to the surface antigens of Raji cell line was confirmed by both immobilizing methods, whereas this MAb had not a noticeable affinity to the MOLT-4 cells. Conclusion: According to the outcomes, the investigated MAb had acceptable affinity and specificity to the target antigens on the cell surface and could be utilized for immuno-detection of CD20-positive intact cells by SPR method. PMID:28761820

Oklahoma's induced seismicity strongly linked to wastewater injection depth

NASA Astrophysics Data System (ADS)

Hincks, Thea; Aspinall, Willy; Cooke, Roger; Gernon, Thomas

2018-03-01

The sharp rise in Oklahoma seismicity since 2009 is due to wastewater injection. The role of injection depth is an open, complex issue, yet critical for hazard assessment and regulation. We developed an advanced Bayesian network to model joint conditional dependencies between spatial, operational, and seismicity parameters. We found that injection depth relative to crystalline basement most strongly correlates with seismic moment release. The joint effects of depth and volume are critical, as injection rate becomes more influential near the basement interface. Restricting injection depths to 200 to 500 meters above basement could reduce annual seismic moment release by a factor of 1.4 to 2.8. Our approach enables identification of subregions where targeted regulation may mitigate effects of induced earthquakes, aiding operators and regulators in wastewater disposal regions.

Helium Bubble Injection Solution To The Cavitation Damage At The Spallation Neutron Source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Francis, M. W.; Ruggles, A. E.

2009-03-10

The Spallation Neutron Source (SNS) is one of the largest science projects in the United States, with total cost near 1.4 Billion Dollars. The limiting factor of the facility had always been assumed to be the lifetime of the target window due to radiation damage. After further investigation, the lifetime of the target was determined not to be limited by radiation damage but by cavitation damage. The cavitation damage derives from pressure waves caused by the beam energy deposition. Vapor bubbles form when low to negative pressures occur in the mercury near the stainless steel target window due to wavemore » interaction with the structure. Collapse of these bubbles can focus wave energy in small liquid jets that erode the window surface. Compressibility of the mercury can be enhanced to reduce the amplitude of the pressure wave caused by the beam energy deposition. To enhance compressibility, small (10 to 30 micron diameter) gas bubbles could be injected into the bulk of the mercury. Solubility and diffusivity parameters of inert gas in mercury are required for a complete mechanical simulation and engineering of these strategies. Using current theoretical models, one obtains a theoretical Henry coefficient of helium in mercury on the order of 3.9E15 Pa-molHg/molHe at 300 K. This low solubility was confirmed by a direct, offline experimental method. Mercury was charged with helium and any pressure change was recorded. Any pressure change was attributed to gas going into solution. Therefore, with the sensitivity of the experiment, a lower limit of 9E12 Pa-molHg/molHe was placed on the mercury-helium system. These values guarantee a stable bubble lifetime needed within the SNS mercury target to mitigate cavitation issues.« less

"The first shot": the context of first injection of illicit drugs, ongoing injecting practices, and hepatitis C infection in Rio de Janeiro, Brazil.

PubMed

Oliveira, Maria de Lourdes Aguiar; Hacker, Mariana A; Oliveira, Sabrina Alberti Nóbrega de; Telles, Paulo Roberto; O, Kycia Maria Rodrigues do; Yoshida, Clara Fumiko Tachibana; Bastos, Francisco I

2006-04-01

The context of first drug injection and its association with ongoing injecting practices and HCV (hepatitis C virus) infection were investigated. Injection drug users (IDUs) (N = 606) were recruited in "drug scenes" (public places, bars) in Rio de Janeiro, Brazil, interviewed, and tested for HCV. Sharing of needles/syringes was more prevalent at the first injection (51.3%) than at the baseline interview (36.8%). Those who shared syringes/needles at first injection were more likely to be currently engaged in direct/indirect sharing practices. Among young injectors (< 30 years), those reporting sharing of needles/ syringes at the first injection were about four times more likely to have been infected by HCV. Hepatitis C virus prevalence among active IDUs (n = 272) was 11%. Prison history and longer duration of drug injection were identified as independent predictors of HCV infection. To effectively curb HCV transmission among IDUs and minimize harms associated with risk behaviors, preventive strategies should target individuals initiating drug injection beginning with their very first injection and discourage the transition from non-injecting use to the self-injection of illicit drugs.

Gold and isotopically enriched platinium targets for the production of radioactive beams of francium

NASA Astrophysics Data System (ADS)

Lipski, A. R.; Orozco, L. A.; Pearson, M. R.; Simsarian, J. E.; Sprouse, G. D.; Zhao, W. Z.

1999-12-01

Au and isotopically enriched Pt targets are discussed for the production of radioactive Fr beams. Target foils, serving also as ionizers, have to be heated in order to enhance the diffusion of atoms to the surface for further extraction and injection into the electrostatic transport system.

Mercury Cavitation Phenomenon in Pulsed Spallation Neutron Sources

DOE Office of Scientific and Technical Information (OSTI.GOV)

Futakawa, Masatoshi; Naoe, Takashi; Kawai, Masayoshi

2008-06-24

Innovative researches will be performed at Materials and Life Science Experimental Facility in J-PARC, in which a mercury target system will be installed as MW-class pulse spallation neutron sources. Proton beams will be injected into mercury target to induce the spallation reaction. At the moment the intense proton beam hits the target, pressure waves are generated in the mercury because of the abrupt heat deposition. The pressure waves interact with the target vessel leading to negative pressure that may cause cavitation along the vessel wall. Localized impacts by micro-jets and/or shock waves which are caused by cavitation bubble collapse imposemore » pitting damage on the vessel wall. The pitting damage which degrades the structural integrity of target vessels is a crucial issue for high power mercury targets. Micro-gas-bubbles injection into mercury may be useful to mitigate the pressure wave and the pitting damage. The visualization of cavitation-bubble and gas-bubble collapse behaviors was carried out by using a high-speed video camera. The differences between them are recognized.« less

Temporary Vascular Occlusion by Rapid Reverse Phase Polymer: A Preliminary In Vitro Study of Retrograde Injection

PubMed Central

Dregelid, Einar

2012-01-01

During vascular surgical operations, there is a need for a simpler and more reliable method of temporary arterial occlusion than those currently employed, especially of heavily calcified arteries. A thermosensitive polymer, LeGoo (LG) (Pluromed, Woburn, MA), has been used successfully for temporary vascular occlusion. It has hitherto been injected by a cannula that has been introduced into the artery to be occluded, here henceforth called the “cannulation method.” Injection into arterial ostia without cannulation, using an injection device that arrests blood flow during the injection, here henceforth called “a retrograde method” may enable temporary hemostasis when ostial stenoses render it impossible to inject LG using the cannulation method. The objective of the present study was to study the feasibility of a retrograde method and to compare it with the cannulation method in an in vitro model, incorporating a narrow orifice to simulate ostial stenosis, using tap water at 37°C instead of blood. The retrograde method of LG injection, using a modified paediatric Foley catheter, turned out to be feasible to produce a durable LG plug more reliably, at higher water pressure and with less deep LG injection than with the cannulation method. PMID:22888352

A HWIL test facility of infrared imaging laser radar using direct signal injection

NASA Astrophysics Data System (ADS)

Wang, Qian; Lu, Wei; Wang, Chunhui; Wang, Qi

2005-01-01

Laser radar has been widely used these years and the hardware-in-the-loop (HWIL) testing of laser radar become important because of its low cost and high fidelity compare with On-the-Fly testing and whole digital simulation separately. Scene generation and projection two key technologies of hardware-in-the-loop testing of laser radar and is a complicated problem because the 3D images result from time delay. The scene generation process begins with the definition of the target geometry and reflectivity and range. The real-time 3D scene generation computer is a PC based hardware and the 3D target models were modeled using 3dsMAX. The scene generation software was written in C and OpenGL and is executed to extract the Z-buffer from the bit planes to main memory as range image. These pixels contain each target position x, y, z and its respective intensity and range value. Expensive optical injection technologies of scene projection such as LDP array, VCSEL array, DMD and associated scene generation is ongoing. But the optical scene projection is complicated and always unaffordable. In this paper a cheaper test facility was described that uses direct electronic injection to provide rang images for laser radar testing. The electronic delay and pulse shaping circuits inject the scenes directly into the seeker's signal processing unit.

Live Imaging of Cell Motility and Actin Cytoskeleton of Individual Neurons and Neural Crest Cells in Zebrafish Embryos

PubMed Central

Andersen, Erica; Asuri, Namrata; Clay, Matthew; Halloran, Mary

2010-01-01

The zebrafish is an ideal model for imaging cell behaviors during development in vivo. Zebrafish embryos are externally fertilized and thus easily accessible at all stages of development. Moreover, their optical clarity allows high resolution imaging of cell and molecular dynamics in the natural environment of the intact embryo. We are using a live imaging approach to analyze cell behaviors during neural crest cell migration and the outgrowth and guidance of neuronal axons. Live imaging is particularly useful for understanding mechanisms that regulate cell motility processes. To visualize details of cell motility, such as protrusive activity and molecular dynamics, it is advantageous to label individual cells. In zebrafish, plasmid DNA injection yields a transient mosaic expression pattern and offers distinct benefits over other cell labeling methods. For example, transgenic lines often label entire cell populations and thus may obscure visualization of the fine protrusions (or changes in molecular distribution) in a single cell. In addition, injection of DNA at the one-cell stage is less invasive and more precise than dye injections at later stages. Here we describe a method for labeling individual developing neurons or neural crest cells and imaging their behavior in vivo. We inject plasmid DNA into 1-cell stage embryos, which results in mosaic transgene expression. The vectors contain cell-specific promoters that drive expression of a gene of interest in a subset of sensory neurons or neural crest cells. We provide examples of cells labeled with membrane targeted GFP or with a biosensor probe that allows visualization of F-actin in living cells1. Erica Andersen, Namrata Asuri, and Matthew Clay contributed equally to this work. PMID:20130524

A novel method to label preformed liposomes with 64Cu for positron emission tomography (PET) imaging.

PubMed

Seo, Jai Woong; Zhang, Hua; Kukis, David L; Meares, Claude F; Ferrara, Katherine W

2008-12-01

Radiolabeling of liposomes with 64Cu (t(1/2)=12.7 h) is attractive for molecular imaging and monitoring drug delivery. A simple chelation procedure, performed at a low temperature and under mild conditions, is required to radiolabel preloaded liposomes without lipid hydrolysis or the release of the encapsulated contents. Here, we report a 64Cu postlabeling method for liposomes. A 64Cu-specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT), was conjugated with an artificial lipid to form a BAT-PEG-lipid. After incorporation of 0.5% (mol/mol) BAT-PEG-lipid during liposome formulation, liposomes were successfully labeled with 64Cu in 0.1 M NH4OAc pH 5 buffer at 35 degrees C for 30-40 min with an incorporation yield as high as 95%. After 48 h of incubation of 64Cu-liposomes in 50/50 serum/PBS solution, more than 88% of the 64Cu label was still associated with liposomes. After injection of liposomal 64Cu in a mouse model, 44+/-6.9, 21+/-2.7, 15+/-2.5, and 7.4+/-1.1 (n=4) % of the injected dose per cubic centimeter remained within the blood pool at 30 min, 18, 28, and 48 h, respectively. The biodistribution at 48 h after injection verified that 7.0+/-0.47 (n=4) and 1.4+/-0.58 (n=3) % of the injected dose per gram of liposomal 64Cu and free 64Cu remained in the blood pool, respectively. Our results suggest that this fast and easy 64Cu labeling of liposomes could be exploited in tracking liposomes in vivo for medical imaging and targeted delivery.

Ultrasensitive analysis of lysergic acid diethylamide and its C-8 isomer in hair by capillary zone electrophoresis in combination with a stacking technique and laser induced fluorescence detection.

PubMed

Airado-Rodríguez, Diego; Cruces-Blanco, Carmen; García-Campaña, Ana M

2015-03-25

This article deals with the development and validation of a novel capillary zone electrophoresis (CZE) with laser induced fluorescence detection method for the analysis of lysergic acid diethylamide (LSD) and its isomer iso-LSD in hair samples. The separation of both analytes has been achieved in less than 13 min in a 72-cm effective length capillary with 75-μm internal diameter. As running buffer 25 mM citrate, pH 6.0 has been employed and separation temperature and voltage of 20 °C and 13 kV respectively, were applied. Field amplified sample injection (FASI) has been employed for on-line sample preconcentration, using ultrapure water containing 117 μM H3PO4 as optimum injection medium. Injection voltage and time have been optimized by means of experimental design, obtaining values of 7 kV and 15s, respectively. Methylergonovine has been employed as internal standard in order to compensate irreproducibility from electrokinetic injection. The analytical method has been applied to hair samples, previous extraction of the target analytes by ultrasound assisted solid-liquid extraction at 40 °C for 2.5 h, employing acetonitrile as extracting solvent. Linear responses were found for LSD and iso-LSD in matrix-matched calibrations from around 0.400 up to 50.0 pg mg(-1). LODs (3 S/N) in the order of 0.100 pg mg(-1) were calculated for both analytes, obtaining satisfactory recovery percentages for this kind of sample. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantitative analysis of fragrance in selectable one dimensional or two dimensional gas chromatography-mass spectrometry with simultaneous detection of multiple detectors in single injection.

PubMed

Tan, Hui Peng; Wan, Tow Shi; Min, Christina Liew Shu; Osborne, Murray; Ng, Khim Hui

2014-03-14

A selectable one-dimensional ((1)D) or two-dimensional ((2)D) gas chromatography-mass spectrometry (GC-MS) system coupled with flame ionization detector (FID) and olfactory detection port (ODP) was employed in this study to analyze perfume oil and fragrance in shower gel. A split/splitless (SSL) injector and a programmable temperature vaporization (PTV) injector are connected via a 2-way splitter of capillary flow technology (CFT) in this selectable (1)D/(2)D GC-MS/FID/ODP system to facilitate liquid sample injections and thermal desorption (TD) for stir bar sorptive extraction (SBSE) technique, respectively. The dual-linked injectors set-up enable the use of two different injector ports (one at a time) in single sequence run without having to relocate the (1)D capillary column from one inlet to another. Target analytes were separated in (1)D GC-MS/FID/ODP and followed by further separation of co-elution mixture from (1)D in (2)D GC-MS/FID/ODP in single injection without any instrumental reconfiguration. A (1)D/(2)D quantitative analysis method was developed and validated for its repeatability - tR; calculated linear retention indices (LRI); response ratio in both MS and FID signal, limit of detection (LOD), limit of quantitation (LOQ), as well as linearity over a concentration range. The method was successfully applied in quantitative analysis of perfume solution at different concentration level (RSD≤0.01%, n=5) and shower gel spiked with perfume at different dosages (RSD≤0.04%, n=5) with good recovery (96-103% for SSL injection; 94-107% for stir bar sorptive extraction-thermal desorption (SBSE-TD). Copyright © 2014 Elsevier B.V. All rights reserved.

Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition.

PubMed

Hua, Susan; Cabot, Peter J

2013-01-01

The peripheral immune-derived opioid analgesic pathway has been well established as a novel target in the clinical pain management of a number of painful pathologies, including acute inflammatory pain, neuropathic pain, and rheumatoid arthritis. Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression, sedation, dependence, tolerance). A randomized, double blind, controlled animal trial. Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes, empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 μL Complete Freund's Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All formulations were administered intravenously via tail vein injection. The dose administered was 200 μL, which equated to 0.8 mg of loperamide HCl for the loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An investigator blinded to the treatment administered assessed the time course of the antinociceptive and anti-inflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes via tail vein injection using liquid scintillation counting (LSC). Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic and anti-inflammatory effects over the 48 hour time course studied following intravenous administration in rats with Complete Freund's Adjuvant-induced inflammation of the paw. All control groups showed no significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into the brain. In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. The study presents a novel approach of opioid delivery specifically to injured tissues for pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting, which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles with other therapeutic compounds for use in other painful conditions.

Ultrasound-guided microinjection into the mouse forebrain in utero at E9.5.

PubMed

Pierfelice, Tarran J; Gaiano, Nicholas

2010-11-13

In utero survival surgery in mice permits the molecular manipulation of gene expression during development. However, because the uterine wall is opaque during early embryogenesis, the ability to target specific parts of the embryo for microinjection is greatly limited. Fortunately, high-frequency ultrasound imaging permits the generation of images that can be used in real time to guide a microinjection needle into the embryonic region of interest. Here we describe the use of such imaging to guide the injection of retroviral vectors into the ventricular system of the mouse forebrain at embryonic day (E) 9.5. This method uses a laparotomy to permit access to the uterine horns, and a specially designed plate that permits host embryos to be bathed in saline while they are imaged and injected. Successful surgeries often result in most or all of the injected embryos surviving to any subsequent time point of interest (embryonically or postnatally). The principles described here can be used with slight modifications to perform injections into the amnionic fluid of E8.5 embryos (thereby permitting infection along the anterior posterior extent of the neural tube, which has not yet closed), or into the ventricular system of the brain at E10.5/11.5. Furthermore, at mid-neurogenic ages (~E13.5), ultrasound imaging can be used direct injection into specific brain regions for viral infection or cell transplantation. The use of ultrasound imaging to guide in utero injections in mice is a very powerful technique that permits the molecular and cellular manipulation of mouse embryos in ways that would otherwise be exceptionally difficult if not impossible.

Intra-articular collagenase injection increases range of motion in a rat knee flexion contracture model

PubMed Central

Wong, Kayleigh; Trudel, Guy; Laneuville, Odette

2018-01-01

Objectives A knee joint contracture, a loss in passive range of motion (ROM), can be caused by prolonged immobility. In a rat knee immobilization flexion contracture model, the posterior capsule was shown to contribute to an irreversible limitation in ROM, and collagen pathways were identified as differentially expressed over the development of a contracture. Collagenases purified from Clostridium histolyticum are currently prescribed to treat Dupuytren’s and Peyronie’s contractures due to their ability to degrade collagen. The potential application of collagenases to target collagen in the posterior capsule was tested in this model. Materials and methods Rats had one hind leg immobilized, developing a knee flexion contracture. After 4 weeks, the immobilization device was removed, and the rats received one 50 µL intra-articular injection of 0.6 mg/mL purified collagenase. Control rats were injected with only the buffer. After 2 weeks of spontaneous remobilization following the injections, ROM was measured with a rat knee arthrometer, and histological sections were immunostained with antibodies against rat collagen types I and III. Results/conclusion Compared with buffer-injected control knees, collagenase-treated knees showed increased ROM in extension by 8.0°±3.8° (p-value <0.05). Immunohistochemical analysis revealed an increase in collagen type III staining (p<0.01) in the posterior capsule of collagenase-treated knees indicating an effect on the extracellular matrix due to the collagenase. Collagen I staining was unchanged (p>0.05). The current study provides experimental evidence for the pharmacological treatment of knee flexion contractures with intra-articular collagenase injection, improving the knee ROM. PMID:29317799

Water quality requirements for sustaining aquifer storage and recovery operations in a low permeability fractured rock aquifer.

PubMed

Page, Declan; Miotliński, Konrad; Dillon, Peter; Taylor, Russel; Wakelin, Steve; Levett, Kerry; Barry, Karen; Pavelic, Paul

2011-10-01

A changing climate and increasing urbanisation has driven interest in the use of aquifer storage and recovery (ASR) schemes as an environmental management tool to supplement conventional water resources. This study focuses on ASR with stormwater in a low permeability fractured rock aquifer and the selection of water treatment methods to prevent well clogging. In this study two different injection and recovery phases were trialed. In the first phase ~1380 m(3) of potable water was injected and recovered over four cycles. In the second phase ~3300 m(3) of treated stormwater was injected and ~2410 m(3) were subsequently recovered over three cycles. Due to the success of the potable water injection cycles, its water quality was used to set pre-treatment targets for harvested urban stormwater of ≤ 0.6 NTU turbidity, ≤ 1.7 mg/L dissolved organic carbon and ≤ 0.2 mg/L biodegradable dissolved organic carbon. A range of potential ASR pre-treatment options were subsequently evaluated resulting in the adoption of an ultrafiltration/granular activated carbon system to remove suspended solids and nutrients which cause physical and biological clogging. ASR cycle testing with potable water and treated stormwater demonstrated that urban stormwater containing variable turbidity (mean 5.5 NTU) and organic carbon (mean 8.3 mg/L) concentrations before treatment could be injected into a low transmissivity fractured rock aquifer and recovered for irrigation supplies. A small decline in permeability of the formation in the vicinity of the injection well was apparent even with high quality water that met turbidity and DOC but could not consistently achieve the BDOC criteria. Copyright © 2011 Elsevier Ltd. All rights reserved.

Radiolabeled arginine-glycine-aspartic acid peptides to image angiogenesis in swine model of hibernating myocardium.

PubMed

Johnson, Lynne L; Schofield, Lorraine; Donahay, Tammy; Bouchard, Mark; Poppas, Athena; Haubner, Roland

2008-07-01

Our aim was to image angiogenesis produced by endomyocardial injection of phVEGF165 in a swine model of hibernating myocardium using [123I]Gluco-arginine-glycine-aspartic acid (RGD) targeting the alphavbeta3 integrins. A noninvasive test to monitor the efficacy of therapy inducing angiogenesis is needed. The interaction between extracellular matrix and endothelial cells in sprouting capillaries is effected primarily by alphavbeta3 integrins that bind through RGD motifs. At 21 +/- 4 days, after left circumflex coronary artery ameroid constrictor placement, 8 swine received endomyocardial injection of 1.2 mg phVEGF165 divided into 6 sites and 6 swine received saline (S) using nonfluoroscopic 3-dimensional endocardial mapping system (Noga)-guided delivery. After 20 +/- 6 days, 13 animals were injected with 6.4 +/- 1.7 mCi [123I]Gluco-RGD, 1 VEGF (vascular endothelial growth factor)-injected animal with I-123-labeled peptide control, and all animals with 2.5 +/- 0.4 mCi of Tl-201 and underwent single-photon emission computed tomography imaging. Blood flow and echocardiographic measurements were made at both time points and tissue analyzed for fibrosis and capillary density by lectin staining. Hibernating myocardium in the ameroid constrictor territory at time of injections was documented by reduced wall thickening compared with remote. Ratio of myocardial blood flow in left circumflex coronary artery/left anterior descending coronary artery territories increased by 15 +/- 11% in the VEGF animals and fell 13 +/- 12% in S-injected (p < 0.01). There was a small increase in wall thickening in constrictor territory after VEGF (8 +/- 17%) while in S-injected animals wall thickening fell by 23 +/- 31% (p = 0.01 vs. VEGF). Lectin staining as percent positive tissue staining for ameroid territory was higher in VEGF-injected compared with S-injected animals (2.5 +/- 1.5% vs. 0.87 +/- 0.52%, p = 0.01). Focal uptake of [123I]Gluco-RGD corresponding to Tl-201 defects was seen in VEGF-injected but not in S-injected animals. [123I]Gluco-RGD uptake in the ameroid territory as percent injected dose correlated with lectin staining (R2 = 0.80, p = 0.002). These data suggest that single-photon emission computed tomography imaging of radiolabeled RGD peptides may be a useful noninvasive method to monitor therapy that induces angiogenesis in the heart.

FeNi nanotubes: perspective tool for targeted delivery

NASA Astrophysics Data System (ADS)

Kaniukov, Egor; Shumskaya, Alena; Yakimchuk, Dzmitry; Kozlovskiy, Artem; Korolkov, Ilya; Ibragimova, Milana; Zdorovets, Maxim; Kadyrzhanov, Kairat; Rusakov, Vyacheslav; Fadeev, Maxim; Lobko, Eugenia; Saunina, Kristina; Nikolaevich, Larisa

2018-05-01

Targeted delivery of drugs and proteins by magnetic field is a promising method to treat cancer that reduces undesired systemic toxicity of drugs. In this method, the therapeutic agent is attached through links to functional groups with magnetic nanostructure and injected into the blood to be transported to the problem area. To provide a local effect of drug treatment, nanostructures are concentrated and fixed in the selected area by the external magnetic field (magnet). After the exposure, carriers are removed from the circulatory system by magnetic field. In this study, Fe20Ni80 nanotubes are considered as carriers for targeted delivery of drugs and proteins. A simple synthesis method is proposed to form these structures by electrodeposition in PET template pores, and structural and magnetic properties are studied in detail. Nanotubes have polycrystalline walls providing mechanical strength of carriers and magnetic anisotropy that allow controlling the nanostructure movement under the exposure of by magnetic field. Moreover, potential advantages of magnetic nanotubes are discussed in comparison with other carrier types. Most sufficient of them is predictable behavior in magnetic field due to the absence of magnetic core, low specific density that allows floating in biological media, and large specific surface area providing the attachment of a larger number of payloads for the targeted delivery. A method of coating nanotube surfaces with PMMA is proposed to exclude possible negative impact of the carrier material and to form functional bonds for the payload connection. Cytotoxicity studies of coated and uncoated nanotubes are carried out to understand their influence on the biological media.

Effects of surface displayed targeting ligand GE11 on liposome distribution and extravasation in tumor.

PubMed

Tang, Hailing; Chen, Xiaojing; Rui, Mengjie; Sun, Wenqiang; Chen, Jian; Peng, Jinliang; Xu, Yuhong

2014-10-06

Targeting ligands displayed on liposome surface had been used to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after IV injection. In this study, we incorporated an EGFR targeting peptide GE11 on liposome surfaces in addition to PEG at different densities and evaluated their targeting properties and antitumor effects. We found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. The inclusion of GE11-PEG-DSPE and PEG-DSPE at 2% and 4% mol ratios in the liposome formulation mediated a rapid accumulation of liposomes within 1 h after IV injection in the tumor tissues surrounding neovascular structures. This is in addition to the EPR effect that was most prominently described for surface PEG modified liposomes. Therefore, despite the fact that the distribution of liposomes into interior tumor tissues was still limited by diffusion, GE11 targeted doxorubicin loaded liposomes showed significantly better antitumor activity in tumor bearing mice as a result of the fast active-targeting efficiency. We anticipate these understandings can benefit further optimization of targeted drug delivery systems for improving efficacy in vivo.

Double-cross hydrostatic pressure sample injection for chip CE: variable sample plug volume and minimum number of electrodes.

PubMed

Luo, Yong; Wu, Dapeng; Zeng, Shaojiang; Gai, Hongwei; Long, Zhicheng; Shen, Zheng; Dai, Zhongpeng; Qin, Jianhua; Lin, Bingcheng

2006-09-01

A novel sample injection method for chip CE was presented. This injection method uses hydrostatic pressure, generated by emptying the sample waste reservoir, for sample loading and electrokinetic force for dispensing. The injection was performed on a double-cross microchip. One cross, created by the sample and separation channels, is used for formation of a sample plug. Another cross, formed by the sample and controlling channels, is used for plug control. By varying the electric field in the controlling channel, the sample plug volume can be linearly adjusted. Hydrostatic pressure takes advantage of its ease of generation on a microfluidic chip, without any electrode or external pressure pump, thus allowing a sample injection with a minimum number of electrodes. The potential of this injection method was demonstrated by a four-separation-channel chip CE system. In this system, parallel sample separation can be achieved with only two electrodes, which is otherwise impossible with conventional injection methods. Hydrostatic pressure maintains the sample composition during the sample loading, allowing the injection to be free of injection bias.

Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

PubMed

Tchou, Julia; Zhao, Yangbing; Levine, Bruce L; Zhang, Paul J; Davis, Megan M; Melenhorst, Jan Joseph; Kulikovskaya, Irina; Brennan, Andrea L; Liu, Xiaojun; Lacey, Simon F; Posey, Avery D; Williams, Austin D; So, Alycia; Conejo-Garcia, Jose R; Plesa, Gabriela; Young, Regina M; McGettigan, Shannon; Campbell, Jean; Pierce, Robert H; Matro, Jennifer M; DeMichele, Angela M; Clark, Amy S; Cooper, Laurence J; Schuchter, Lynn M; Vonderheide, Robert H; June, Carl H

2017-12-01

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 7 or 3 × 10 8 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR . ©2017 American Association for Cancer Research.

The cardiovascular effects of a chimeric opioid peptide based on morphiceptin and PFRTic-NH2.

PubMed

Li, Meixing; Zhou, Lanxia; Ma, Guoning; Cao, Shuo; Dong, Shouliang

2013-01-01

MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection. Copyright © 2012 Elsevier Inc. All rights reserved.

Determination of eight illegal drugs in human urine by combination of magnetic solid-phase extraction with capillary zone electrophoresis.

PubMed

Chen, Ming-Luan; Suo, Li-Li; Gao, Qiang; Feng, Yu-Qi

2011-08-01

Using magnetite/silica/poly(methacrylic acid-co-ethylene glycol dimethacrylate) (Fe(3)O(4)/SiO(2)/poly(MAA-co-EDMA)) magnetic microspheres, a rapid and high-throughput magnetic solid-phase extraction coupled with capillary zone electrophoresis (MSPE-CZE) method was developed for the determination of illegal drugs (ketamine, amphetamines, opiates, and metabolites). The MSPE of target analytes could be completed within 2 min, and the eight target analytes could be baseline separated within 15 min by CZE with 30 mM phosphate buffer solution (PBS, pH 2.0) containing 15% v/v ACN as background electrolyte. Furthermore, hydrodynamic injection with field-amplified sample stacking (FASS) was employed to enhance the sensitivity of this MSPE-CZE method. Under such optimal conditions, the limits of detection for the eight target analytes ranged from 0.015 to 0.105 μg/mL. The application feasibility of MSPE-CZE in illegal drugs monitoring was demonstrated by analyzing urine samples, and the recoveries of target drugs for the spiked sample ranging from 85.4 to 110.1%. The method reproducibility was tested by evaluating the intra- and interday precisions, and relative standard deviations of <10.3 and 12.4%, respectively, were obtained. To increase throughput of the analysis, a home-made MSPE array that has potential application to the treatment of 96 samples simultaneously was used. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Waterflooding injectate design systems and methods

DOEpatents

Brady, Patrick V.; Krumhansl, James L.

2016-12-13

A method of recovering a liquid hydrocarbon using an injectate includes recovering the liquid hydrocarbon through primary extraction. Physico-chemical data representative of electrostatic interactions between the liquid hydrocarbon and the reservoir rock are measured. At least one additive of the injectate is selected based on the physico-chemical data. The method includes recovering the liquid hydrocarbon from the reservoir rock through secondary extraction using the injectate.

Efficient mutagenesis by Cas9 protein-mediated oligonucleotide insertion and large-scale assessment of single-guide RNAs.

PubMed

Gagnon, James A; Valen, Eivind; Thyme, Summer B; Huang, Peng; Akhmetova, Laila; Ahkmetova, Laila; Pauli, Andrea; Montague, Tessa G; Zimmerman, Steven; Richter, Constance; Schier, Alexander F

2014-01-01

The CRISPR/Cas9 system has been implemented in a variety of model organisms to mediate site-directed mutagenesis. A wide range of mutation rates has been reported, but at a limited number of genomic target sites. To uncover the rules that govern effective Cas9-mediated mutagenesis in zebrafish, we targeted over a hundred genomic loci for mutagenesis using a streamlined and cloning-free method. We generated mutations in 85% of target genes with mutation rates varying across several orders of magnitude, and identified sequence composition rules that influence mutagenesis. We increased rates of mutagenesis by implementing several novel approaches. The activities of poor or unsuccessful single-guide RNAs (sgRNAs) initiating with a 5' adenine were improved by rescuing 5' end homogeneity of the sgRNA. In some cases, direct injection of Cas9 protein/sgRNA complex further increased mutagenic activity. We also observed that low diversity of mutant alleles led to repeated failure to obtain frame-shift mutations. This limitation was overcome by knock-in of a stop codon cassette that ensured coding frame truncation. Our improved methods and detailed protocols make Cas9-mediated mutagenesis an attractive approach for labs of all sizes.

Zinc phthalocyanine-loaded PLGA biodegradable nanoparticles for photodynamic therapy in tumor-bearing mice.

PubMed

Fadel, Maha; Kassab, Kawser; Fadeel, Doa Abdel

2010-03-01

Nanoparticles formulated from the biodegradable copolymer poly(lactic-coglycolic acid) (PLGA) were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting of zinc(II) phthalocyanine (ZnPc) for photodynamic therapy. Three ZnPc nanoparticle formulations were prepared using a solvent emulsion evaporation method and the influence of sonication time on nanoparticle shape, encapsulation and size distribution, in vitro release, and in vivo photodynamic efficiency in tumor-bearing mice were studied. Sonication time did not affect the process yield or encapsulation efficiency, but did affect significantly the particle size. Sonication for 20 min reduced the mean particle size to 374.3 nm and the in vitro release studies demonstrated a controlled release profile of ZnPc. Tumor-bearing mice injected with ZnPc nanoparticles exhibited significantly smaller mean tumor volume, increased tumor growth delay and longer survival compared with the control group and the group injected with free ZnPc during the time course of the experiment. Histopathological examination of tumor from animals treated with PLGA ZnPc showed regression of tumor cells, in contrast to those obtained from animals treated with free ZnPc. The results indicate that ZnPc encapsulated in PLGA nanoparticles is a successful delivery system for improving photodynamic activity in the target tissue.

Transcutaneous vaccination via laser microporation

PubMed Central

Weiss, Richard; Hessenberger, Michael; Kitzmüller, Sophie; Bach, Doris; Weinberger, Esther E.; Krautgartner, Wolf D.; Hauser-Kronberger, Cornelia; Malissen, Bernard; Boehler, Christof; Kalia, Yogeshvar N.; Thalhamer, Josef; Scheiblhofer, Sandra

2012-01-01

Driven by constantly increasing knowledge about skin immunology, vaccine delivery via the cutaneous route has recently gained renewed interest. Considering its richness in immunocompetent cells, targeting antigens to the skin is considered to be more effective than intramuscular or subcutaneous injections. However, circumvention of the superficial layer of the skin, the stratum corneum, represents the major challenge for cutaneous immunization. An optimal delivery method has to be effective and reliable, but also highly adaptable to specific demands, should avoid the use of hypodermic needles and the requirement of specially trained healthcare workers. The P.L.E.A.S.E.® (Precise Laser Epidermal System) device employed in this study for creation of aqueous micropores in the skin fulfills these prerequisites by combining the precision of its laser scanning technology with the flexibility to vary the number, density and the depth of the micropores in a user-friendly manner. We investigated the potential of transcutaneous immunization via laser-generated micropores for induction of specific immune responses and compared the outcomes to conventional subcutaneous injection. By targeting different layers of the skin we were able to bias polarization of T cells, which could be modulated by addition of adjuvants. The P.L.E.A.S.E.® device represents a highly effective and versatile platform for transcutaneous vaccination. PMID:22750193

Gold nanoparticle-DNA aptamer composites as a universal carrier for in vivo delivery of biologically functional proteins.

PubMed

Ryou, Sang-Mi; Yeom, Ji-Hyun; Kang, Hyo Jung; Won, Miae; Kim, Jin-Sik; Lee, Boeun; Seong, Maeng-Je; Ha, Nam-Chul; Bae, Jeehyeon; Lee, Kangseok

2014-12-28

Although the delivery of biologically functional protein(s) into mammalian cells could be of tremendous value to biomedical research, the development of such technology has been hindered by the lack of a safe and effective delivery method. Here, we present a simple, efficient, and versatile gold nanoparticle-DNA aptamer conjugate (AuNP-Apt)-based system, with nanoblock-like properties, that allows any recombinant protein to be loaded without additional modifications and delivered into mammalian living systems. AuNP-Apt-based protein delivery system was able to deliver various proteins into variety of cell types in vitro without showing cytotoxicity. This AuNP-Apt system was also effective for the local and systemic targeted delivery of proteins in vivo. A local injection of the AuNP-Apt loaded with the apoptosis-inducing BIM protein efficiently inhibited the growth of xenograft tumors in mice. Furthermore, an intravenous injection of AuNP-Apt loaded with both epidermal growth factor (EGF) and BIM resulted in the targeted delivery of BIM into a xenograft tumor derived from EGF receptor-overexpressing cancer cells with no detectable systemic toxicity. Our findings show that this system can serve as an innovative platform for the development of protein-based biomedical applications. Copyright © 2014 Elsevier B.V. All rights reserved.

DNA nanocarriers for systemic administration: characterization and in vivo bioimaging in healthy mice.

PubMed

David, Stephanie; Passirani, Catherine; Carmoy, Nathalie; Morille, Marie; Mevel, Mathieu; Chatin, Benoit; Benoit, Jean-Pierre; Montier, Tristan; Pitard, Bruno

2013-01-08

We hereby present different DNA nanocarriers consisting of new multimodular systems (MMS), containing the cationic lipid dioleylaminesuccinylparomomycin (DNA MMS DOSP), or bis (guanidinium)-tren-cholesterol (DNA MMS BGTC), and DNA lipid nanocapsules (DNA LNCs). Active targeting of the asialoglycoprotein receptor (ASGP-R) using galactose as a ligand for DNA MMS (GAL DNA MMS) and passive targeting using a polyethylene glycol coating for DNA LNCs (PEG DNA LNCs) should improve the properties of these DNA nanocarriers. All systems were characterized via physicochemical methods and the DNA payload of DNA LNCs was quantified for the first time. Afterwards, their biodistribution in healthy mice was analyzed after encapsulation of a fluorescent dye via in vivo biofluorescence imaging (BFI), revealing various distribution profiles depending on the cationic lipid used and their surface characteristics. Furthermore, the two vectors with the best prolonged circulation profile were administered twice in healthy mice revealing that the new DNA MMS DOSP vectors showed no toxicity and the same distribution profile for both injections, contrary to PEG DNA LNCs which showed a rapid clearance after the second injection, certainly due to the accelerated blood clearance phenomenon.Molecular Therapy - Nucleic Acids (2013) 2, e64; doi:10.1038/mtna.2012.56; published online 8 January 2013.

Investigating the weight ratio variation of alginate-hydroxyapatite composites for vertebroplasty method bone filler material

NASA Astrophysics Data System (ADS)

Lestari, Gusti Ruri; Yuwono, Akhmad Herman; Sofyan, Nofrijon; Ramahdita, Ghiska

2017-02-01

One of the newly developed methods for curing spinal fracture due to osteoporosis is vertebroplasty. The method is basically based on injection of special material directly to the fractured spine in order to commence the formation of new bone. Therefore, appropriate injectable materials are very important to the curing success. In this study, injectable alginate-hydroxyapatite (HA) composites were fabricated varying the weight percentage of alginate upon synthesis procedure. The result of injection capability and compressive tests as well as Fourier transform infrared (FTIR) spectroscopy and scanning electron microscope (SEM) suggested that bone filler composite containing 60 wt% alginate is the optimum composition obtaining a compressive modulus up to 0.15 MPa, injection capability of more than 85% and morphology with uniform porous and fibrous structure. This injectable composite fabrication process can be used for the development of injectable materials system for vertebroplasty method.

Acupuncture injection for field amplified sample stacking and glass microchip-based capillary gel electrophoresis.

PubMed

Ha, Ji Won; Hahn, Jong Hoon

2017-02-01

Acupuncture sample injection is a simple method to deliver well-defined nanoliter-scale sample plugs in PDMS microfluidic channels. This acupuncture injection method in microchip CE has several advantages, including minimization of sample consumption, the capability of serial injections of different sample solutions into the same microchannel, and the capability of injecting sample plugs into any desired position of a microchannel. Herein, we demonstrate that the simple and cost-effective acupuncture sample injection method can be used for PDMS microchip-based field amplified sample stacking in the most simplified straight channel by applying a single potential. We achieved the increase in electropherogram signals for the case of sample stacking. Furthermore, we present that microchip CGE of ΦX174 DNA-HaeⅢ digest can be performed with the acupuncture injection method on a glass microchip while minimizing sample loss and voltage control hardware. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The evaluation of the optimization design and application effect of same-well-injection-production technique’s injection-production circulatory system

NASA Astrophysics Data System (ADS)

Guoxing, Zheng; Minghu, Jiang; Hongliang, Gong; Nannan, Zhang; Jianguang, Wei

2018-02-01

According to basic principles of combining series of strata and demands of same-well injection-production technique, the optimization designing method of same-well injection-production technique’s injection-production circulatory system is given. Based on oil-water two-phase model with condition of arbitrarily well network, a dynamic forecast method for the application of same-well injection-production reservoir is established with considering the demands and capacity of same-well injection-production technique, sample wells are selected to launch the forecast evaluation and analysis of same-well injection-production reservoir application’s effect. Results show: single-test-well composite water cut decreases by 4.7% and test-well-group composite water cut decreases by 1.56% under the condition of basically invariant ground water injection rate. The method provides theoretical support for the proof of same-well injection-production technique’s reservoir development improving effect and further tests.

Solution mining systems and methods for treating hydrocarbon containing formations

DOEpatents

Vinegar, Harold J [Bellaire, TX; de Rouffignac, Eric Pierre [Rijswijk, NL; Schoeling, Lanny Gene [Katy, TX

2009-07-14

A method for treating an oil shale formation comprising nahcolite is disclosed. The method includes providing a first fluid to a portion of the formation through at least two injection wells. A second fluid is produced from the portion through at least one injection well until at least two injection wells are interconnected such that fluid can flow between the two injection wells. The second fluid includes at least some nahcolite dissolved in the first fluid. The first fluid is injected through one of the interconnected injection wells. The second fluid is produced from at least one of the interconnected injection wells. Heat is provided from one or more heaters to the formation to heat the formation. Hydrocarbon fluids are produced from the formation.

Intralesional vincristine combined with cryotherapy for recalcitrant verrucas.

PubMed

Lee, Jong-Rok; Youn, Jeong-Hwan; Roh, Joo-Young

2011-01-01

Verrucas are often recalcitrant to conventional cryotherapy. Since 1970, intralesional bleomycin has been used off-label by dermatologists. But in some cases, the results of intralesional bleomycin were disappointing. Vincristine is a well-known vinca alkaloid antiblastic drug that has been used for treating hematological neoplasm and nephroblastomas. It was reported good efficacy of intralesional vincristine for treating nodular lesion in classic Kaposi sarcoma. Its use in epithelial neoplasm and Kaposi sarcoma may support its efficacy in recalcitrant verrucas. The three patients selected for the study presented severe verrucas on foot, and they had already undergone cryotherapy several times and there was no improvement. They got intralesional vincristine injection on their verrucas. The target lesion was infiltrated with 0.03 mL of vincristine sulphate at a concentration of 1 µg/mL. The injected amount of vincristine was proportional to the diameter of the nodule. After two treatments had been completed, there was a great decrease of lesion size compared with the other lesions. The three patients complained of pain lasting for several days. This pain was generally well tolerated. Intralesional vincristine injection on verruca is an effective and rapid novel method, and when combined with cryotherapy, shows excellent therapeutic response. © 2011 Wiley Periodicals, Inc.

Hydraulic Fracturing for Oil and Gas: Impacts from the ...

EPA Pesticide Factsheets

This final report provides a review and synthesis of available scientific information concerning the relationship between hydraulic fracturing activities and drinking water resources in the United States. The report is organized around activities in the hydraulic fracturing water cycle and their potential to impact drinking water resources.  The stages include: (1) acquiring water to be used for hydraulic fracturing (Water Acquisition), (2) mixing the water with chemical additives to prepare hydraulic fracturing fluids (Chemical Mixing), (3) injecting the hydraulic fracturing fluids into the production well to create fractures in the targeted production zone (Well Injection), (4) collecting the wastewater that returns through the well after injection (Produced Water Handling), and (5) managing the wastewater via disposal or reuse methods (Wastewater Disposal and Reuse). EPA found scientific evidence that hydraulic fracturing activities can impact drinking water resources under some circumstances. The report identifies certain conditions under which impacts from hydraulic fracturing activities can be more frequent or severe: Water withdrawals for hydraulic fracturing in times or areas of low water availability, particularly in areas with limited or declining groundwater resources; Spills during the handling of hydraulic fracturing fluids and chemicals or produced water that result in large volumes or high concentrations of chem

Dual-Energy CT Imaging of Tumor Liposome Delivery After Gold Nanoparticle-Augmented Radiation Therapy

PubMed Central

Ashton, Jeffrey R.; Castle, Katherine D.; Qi, Yi; Kirsch, David G.; West, Jennifer L.; Badea, Cristian T.

2018-01-01

Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and computed tomography (CT) imaging. AuNPs absorb x-rays and subsequently release low-energy, short-range photoelectrons during external beam radiation therapy (RT), increasing the local radiation dose. When AuNPs are near tumor vasculature, the additional radiation dose can lead to increased vascular permeability. This work focuses on understanding how tumor vascular permeability is influenced by AuNP-augmented RT, and how this effect can be used to improve the delivery of nanoparticle chemotherapeutics. Methods: Dual-energy CT was used to quantify the accumulation of both liposomal iodine and AuNPs in tumors following AuNP-augmented RT in a mouse model of primary soft tissue sarcoma. Mice were injected with non-targeted AuNPs, RGD-functionalized AuNPs (vascular targeting), or no AuNPs, after which they were treated with varying doses of RT. The mice were injected with either liposomal iodine (for the imaging study) or liposomal doxorubicin (for the treatment study) 24 hours after RT. Increased tumor liposome accumulation was assessed by dual-energy CT (iodine) or by tracking tumor treatment response (doxorubicin). Results: A significant increase in vascular permeability was observed for all groups after 20 Gy RT, for the targeted and non-targeted AuNP groups after 10 Gy RT, and for the vascular-targeted AuNP group after 5 Gy RT. Combining targeted AuNPs with 5 Gy RT and liposomal doxorubicin led to a significant tumor growth delay (tumor doubling time ~ 8 days) compared to AuNP-augmented RT or chemotherapy alone (tumor doubling time ~3-4 days). Conclusions: The addition of vascular-targeted AuNPs significantly improved the treatment effect of liposomal doxorubicin after RT, consistent with the increased liposome accumulation observed in tumors in the imaging study. Using this approach with a liposomal drug delivery system can increase specific tumor delivery of chemotherapeutics, which has the potential to significantly improve tumor response and reduce the side effects of both RT and chemotherapy. PMID:29556356

Injection-depth-locking axial motion guided handheld micro-injector using CP-SSOCT.

PubMed

Cheon, Gyeong Woo; Huang, Yong; Kwag, Hye Rin; Kim, Ki-Young; Taylor, Russell H; Gehlbach, Peter L; Kang, Jin U

2014-01-01

This paper presents a handheld micro-injector system using common-path swept source optical coherence tomography (CP-SSOCT) as a distal sensor with highly accurate injection-depth-locking. To achieve real-time, highly precise, and intuitive freehand control, the system used graphics processing unit (GPU) to process the oversampled OCT signal with high throughput and a smart customized motion monitoring control algorithm. A performance evaluation was conducted with 60-insertions and fluorescein dye injection tests to show how accurately the system can guide the needle and lock to the target depth. The evaluation tests show our system can guide the injection needle into the desired depth with 4.12 um average deviation error while injecting 50 nl of fluorescein dye.

Fully integrated high-speed intravascular optical coherence tomography/near-infrared fluorescence structural/molecular imaging in vivo using a clinically available near-infrared fluorescence-emitting indocyanine green to detect inflamed lipid-rich atheromata in coronary-sized vessels.

PubMed

Lee, Sunki; Lee, Min Woo; Cho, Han Saem; Song, Joon Woo; Nam, Hyeong Soo; Oh, Dong Joo; Park, Kyeongsoon; Oh, Wang-Yuhl; Yoo, Hongki; Kim, Jin Won

2014-08-01

Lipid-rich inflamed coronary plaques are prone to rupture. The purpose of this study was to assess lipid-rich inflamed plaques in vivo using fully integrated high-speed optical coherence tomography (OCT)/near-infrared fluorescence (NIRF) molecular imaging with a Food and Drug Administration-approved indocyanine green (ICG). An integrated high-speed intravascular OCT/NIRF imaging catheter and a dual-modal OCT/NIRF system were constructed based on a clinical OCT platform. For imaging lipid-rich inflamed plaques, the Food and Drug Administration-approved NIRF-emitting ICG (2.25 mg/kg) or saline was injected intravenously into rabbit models with experimental atheromata induced by balloon injury and 12- to 14-week high-cholesterol diets. Twenty minutes after injection, in vivo OCT/NIRF imaging of the infrarenal aorta and iliac arteries was acquired only under contrast flushing through catheter (pullback speed up to ≤20 mm/s). NIRF signals were strongly detected in the OCT-visualized atheromata of the ICG-injected rabbits. The in vivo NIRF target-to-background ratio was significantly larger in the ICG-injected rabbits than in the saline-injected controls (P<0.01). Ex vivo peak plaque target-to-background ratios were significantly higher in ICG-injected rabbits than in controls (P<0.01) on fluorescence reflectance imaging, which correlated well with the in vivo target-to-background ratios (P<0.01; r=0.85) without significant bias (0.41). Cellular ICG uptake, correlative fluorescence microscopy, and histopathology also corroborated the in vivo imaging findings. Integrated OCT/NIRF structural/molecular imaging with a Food and Drug Administration -approved ICG accurately identified lipid-rich inflamed atheromata in coronary-sized vessels. This highly translatable dual-modal imaging approach could enhance our capabilities to detect high-risk coronary plaques. © 2014 American Heart Association, Inc.

Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials

PubMed Central

2017-01-01

Injectable hydrogels have gained popularity as a vehicle for the delivery of cells, growth factors, and other molecules to localize and improve their retention at the injection site, as well as for the mechanical bulking of tissues. However, there are many factors, such as viscosity, storage and loss moduli, and injection force, to consider when evaluating hydrogels for such applications. There are now numerous tools that can be used to quantitatively assess these factors, including for shear-thinning hydrogels because their properties change under mechanical load. Here, we describe relevant rheological tests and ways to measure injection force using a force sensor or a mechanical testing machine toward the evaluation of injectable hydrogels. Injectable, shear-thinning hydrogels can be used in a variety of clinical applications, and as an example we focus on methods for injection into the heart, where an understanding of injection properties and mechanical forces is imperative for consistent hydrogel delivery and retention. We discuss methods for delivery of hydrogels to mouse, rat, and pig hearts in models of myocardial infarction, and compare methods of tissue postprocessing for hydrogel preservation. Our intent is that the methods described herein can be helpful in the design and assessment of shear-thinning hydrogels for widespread biomedical applications. PMID:29250593

Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvβ3-expressing tumours.

PubMed

Bozon-Petitprin, A; Bacot, S; Gauchez, A S; Ahmadi, M; Bourre, J C; Marti-Batlle, D; Perret, P; Broisat, A; Riou, L M; Claron, M; Boturyn, D; Fagret, D; Ghezzi, Catherine; Vuillez, J P

2015-02-01

The αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β(-) emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy.

Injectable contraceptive sales at licensed chemical seller shops in ghana: access and reported use in rural and periurban communities.

PubMed

Lebetkin, Elena; Orr, Tracy; Dzasi, Kafui; Keyes, Emily; Shelus, Victoria; Mensah, Stephen; Nagai, Henry; Stanback, John

2014-03-01

Most women in Ghana obtain oral contraceptives and condoms from shops run by licensed chemical sellers, but such shops are not legally permitted to sell the country's most widely used method, the injectable. Allowing shops to sell the injectable could increase access to and use of the method. In 2012-2013, semistructured telephone interviews were conducted among convenience samples of 94 licensed chemical seller shop operators in two districts who were trained to sell the injectable and of 298 women who purchased the method from these shops. Follow-up interviews were conducted with 92 clients approximately three months after their initial injectable purchase. Ninety-seven percent of shop operators reported selling the injectable, and 94% felt sufficiently trained to provide family planning methods and services. Virtually all sellers (99%) referred clients to a hospital or health facility for injection; none provided injections themselves. Fifty-six percent of injectable clients were new family planning users. Of those who completed a follow-up interview, 79% had purchased the injectable again from a shop. Virtually all clients (97%) reported getting their injection at the health facility to which they were referred by the seller. Women cited trust, convenience and commodities being in stock as key reasons for purchasing from a shop. Licensed chemical seller shop operators can safely sell the injectable and refer clients to health facilities for screening, counseling and injection.

Optimisation of warpage on plastic injection moulding part using response surface methodology (RSM) and genetic algorithm method (GA)

NASA Astrophysics Data System (ADS)

Miza, A. T. N. A.; Shayfull, Z.; Nasir, S. M.; Fathullah, M.; Hazwan, M. H. M.

2017-09-01

In this study, Computer Aided Engineering was used for injection moulding simulation. The method of Design of experiment (DOE) was utilize according to the Latin Square orthogonal array. The relationship between the injection moulding parameters and warpage were identify based on the experimental data that used. Response Surface Methodology (RSM) was used as to validate the model accuracy. Then, the RSM and GA method were combine as to examine the optimum injection moulding process parameter. Therefore the optimisation of injection moulding is largely improve and the result shown an increasing accuracy and also reliability. The propose method by combining RSM and GA method also contribute in minimising the warpage from occur.

Incorporating geographic settings into a social network analysis of injection drug use and bloodborne pathogen prevalence.

PubMed

Wylie, John L; Shah, Lena; Jolly, Ann

2007-09-01

Using social network analysis, we investigated how communal meeting places can link injection drug user (IDU) populations and create opportunities for the transmission of bloodborne pathogens. In our locale, specific hotels played a key role in the injection drug scene. Within this hotel network some IDU injected at only one hotel while others injected at multiple hotels; this latter group potentially acted as spatial bridges linking relatively distinct hotel networks. Pathogen prevalence showed a gradation with the highest prevalence occurring at the centre of the network. Consistent with pathogen prevalence, people most central to the network were more likely to engage in risky injection practices. Incorporating geographic place into analyses involving IDU can contribute to an understanding of pathogen transmission patterns in an area and assist public health efforts to develop targeted intervention programs.

Tumor-homing peptides as tools for targeted delivery of payloads to the placenta

PubMed Central

King, Anna; Ndifon, Cornelia; Lui, Sylvia; Widdows, Kate; Kotamraju, Venkata R.; Agemy, Lilach; Teesalu, Tambet; Glazier, Jocelyn D.; Cellesi, Francesco; Tirelli, Nicola; Aplin, John D.; Ruoslahti, Erkki; Harris, Lynda K.

2016-01-01

The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics. PMID:27386551

Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates

PubMed Central

Chun, Seung J.; Norris, Daniel A.; Hung, Gene; Lee, Sam; Matson, John; Fey, Robert A.; Gaus, Hans; Hua, Yimin; Grundy, John S.; Krainer, Adrian R.; Henry, Scott P.; Bennett, C. Frank

2014-01-01

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443–mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development. PMID:24784568

Identification and characterization of a dual-acting antinematodal agent against the pinewood nematode, Bursaphelenchus xylophilus.

PubMed

Oh, Wan-Suk; Jeong, Pan-Young; Joo, Hyoe-Jin; Lee, Jeong-Eui; Moon, Yil-Seong; Cheon, Hyang-Mi; Kim, Jung-Ho; Lee, Yong-Uk; Shim, Yhong-Hee; Paik, Young-Ki

2009-11-11

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+) channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.

Syringe-Injectable Electronics with a Plug-and-Play Input/Output Interface.

PubMed

Schuhmann, Thomas G; Yao, Jun; Hong, Guosong; Fu, Tian-Ming; Lieber, Charles M

2017-09-13

Syringe-injectable mesh electronics represent a new paradigm for brain science and neural prosthetics by virtue of the stable seamless integration of the electronics with neural tissues, a consequence of the macroporous mesh electronics structure with all size features similar to or less than individual neurons and tissue-like flexibility. These same properties, however, make input/output (I/O) connection to measurement electronics challenging, and work to-date has required methods that could be difficult to implement by the life sciences community. Here we present a new syringe-injectable mesh electronics design with plug-and-play I/O interfacing that is rapid, scalable, and user-friendly to nonexperts. The basic design tapers the ultraflexible mesh electronics to a narrow stem that routes all of the device/electrode interconnects to I/O pads that are inserted into a standard zero insertion force (ZIF) connector. Studies show that the entire plug-and-play mesh electronics can be delivered through capillary needles with precise targeting using microliter-scale injection volumes similar to the standard mesh electronics design. Electrical characterization of mesh electronics containing platinum (Pt) electrodes and silicon (Si) nanowire field-effect transistors (NW-FETs) demonstrates the ability to interface arbitrary devices with a contact resistance of only 3 Ω. Finally, in vivo injection into mice required only minutes for I/O connection and yielded expected local field potential (LFP) recordings from a compact head-stage compatible with chronic studies. Our results substantially lower barriers for use by new investigators and open the door for increasingly sophisticated and multifunctional mesh electronics designs for both basic and translational studies.

Demonstration of elevation and localization of Rho-kinase activity in the brain of a rat model of cerebral infarction.

PubMed

Yano, Kazuo; Kawasaki, Koh; Hattori, Tsuyoshi; Tawara, Shunsuke; Toshima, Yoshinori; Ikegaki, Ichiro; Sasaki, Yasuo; Satoh, Shin-ichi; Asano, Toshio; Seto, Minoru

2008-10-10

Evidence that Rho-kinase is involved in cerebral infarction has accumulated. However, it is uncertain whether Rho-kinase is activated in the brain parenchyma in cerebral infarction. To answer this question, we measured Rho-kinase activity in the brain in a rat cerebral infarction model. Sodium laurate was injected into the left internal carotid artery, inducing cerebral infarction in the ipsilateral hemisphere. At 6 h after injection, increase of activating transcription factor 3 (ATF3) and c-Fos was found in the ipsilateral hemisphere, suggesting that neuronal damage occurs. At 0.5, 3, and 6 h after injection of laurate, Rho-kinase activity in extracts of the cerebral hemispheres was measured by an ELISA method. Rho-kinase activity in extracts of the ipsilateral hemisphere was significantly increased compared with that in extracts of the contralateral hemisphere at 3 and 6 h but not 0.5 h after injection of laurate. Next, localization of Rho-kinase activity was evaluated by immunohistochemical analysis in sections of cortex and hippocampus including infarct area 6 h after injection of laurate. Staining for phosphorylation of myosin-binding subunit (phospho-MBS) and myosin light chain (phospho-MLC), substrates of Rho-kinase, was elevated in neuron and blood vessel, respectively, in ipsilateral cerebral sections, compared with those in contralateral cerebral sections. These findings indicate that Rho-kinase is activated in neuronal and vascular cells in a rat cerebral infarction model, and suggest that Rho-kinase could be an important target in the treatment of cerebral infarction.

Col2-Cre and tamoxifen-inducible Col2-CreER target different cell populations in the knee joint

PubMed Central

Nagao, Masashi; Cheong, Chan Wook; Olsen, Bjorn

2015-01-01

Objective Collagen type 2 (Col2)-Cre or tamoxifen-inducible Col2-CreER transgenic mouse lines have been used for studies to explore the cellular and molecular pathogenesis of osteoarthritis (OA). The purpose of this study is to investigate whether the targeted cells are the same or different in the two mouse lines. Methods We crossed tamoxifen inducible Col2-CreER and Col2-Cre mice with Rosa tdTomato reporter mice and analyzed the labeling patterns at different time points. Results In the Col2-CreER mice, 90.8 [95% confidence interval (CI) (88.3, 93.2)] and 82.8 (77.4, 88.3) % of the articular surface cells are Tomato positive when tamoxifen was administered at 2 and 2.5 weeks of age and strong activity was observed even 4.5 months after injection. However, 46.0 (32.8, 59.1) and 22.2 (11.7, 32.6) % of the surface cells were Tomato positive when tamoxifen was administered at 3 and 4 weeks of age, respectively. Little to no Tomato activity in the articular surface cells was observed when tamoxifen was administered at 8 weeks of age. At any stage of tamoxifen injection, the Tomato activity was detected in growth plate and epiphyseal bone in addition to articular chondrocytes, but little in endothelium and not in the synovium and ligament. In contrast, the targeted tissues in the Col2-Cre mouse line were articular cartilage, growth plate, meniscus, endosteum, ligament, bone and synovium. Conclusions This study demonstrates that the pattern of targeted cells in the inducible Col2-CreER mice are partially overlapping with but different from that of targeted cells in Col2-Cre mice and the pattern varies dependent on when tamoxifen is administered. PMID:26256767

The Frio Brine Pilot Experiment Managing CO2 Sequestration in a Brine Formation

NASA Astrophysics Data System (ADS)

Sakurai, S.

2005-12-01

Funded by the U.S. Department of Energy National Energy Technology Laboratory, the Frio Brine Pilot Experiment was begun in 2002. The increase in greenhouse gas emissions, such as carbon dioxide (CO2), is thought to be a major cause of climate change. Sequestration of CO2 in saline aquifers below and separate from fresh water is considered a promising method of reducing CO2 emissions. The objectives of the experiment are to (1) demonstrate CO2 can be injected into a brine formation safely; (2) measure subsurface distribution of injected CO2; (3) test the validity of conceptual, hydrologic, and geochemical models, and (4) develop experience necessary for larger scale CO2 injection experiments. The Bureau of Economic Geology (BEG) is the leading institution on the project and is collaborating with many national laboratories and private institutes. BEG reviewed many saline formations in the US to identify candidates for CO2 storage. The Frio Formation was selected as a target that could serve a large part of the Gulf Coast and site was selected for a brine storage pilot experiment in the South Liberty field, Dayton, Texas. Most wells were drilled in the 1950's, and the fluvial sandstone of the upper Frio Formation in the Oligocene is our target, at a depth of 5,000 ft. An existing well was used as the observation well. A new injection well was drilled 100 ft away, and 30 ft downdip from the observation well. Conventional cores were cut, and analysis indicated 32 to 35 percent porosity and 2,500 md permeability. Detailed core description was valuable as better characterization resulted in design improvements. A bed bisecting the interval originally thought to be a significant barrier to flow is a sandy siltstone having a permeability of about 100 md. As a result, the upper part of the sandstone was perforated. Because of changes in porosity, permeability, and the perforation zone, input for the simulation model was updated and the model was rerun to estimate timing of CO2 breakthrough and saturation changes. A pulsed neutron tool was selected as the primary wireline log for monitoring saturation changes, because of high formation water salinity, along with high porosity. Baseline logs were recorded as preinjection values. We started injection of CO2 on October 4, 2004, and injected 1,600 tons of CO2 for 10 days. Breakthrough of CO2 to the observation well was observed on the third day by geochemical measurement of recovered fluids, including gas analysis and decreased pH value. Multiple capture logs were run to monitor saturation changes. The first log run after CO2 breakthrough on the fourth day showed a significant decrease in sigma was recorded within the upper part of the porous section (6 ft) correlative with the injection interval. Postinjection logs were compared with baseline logs to determine CO2 distribution as CO2 migrated away from the injection point. The dipole acoustic tool was used to estimate saturation changes to improve geophysical data interpretation using VSP and crosswell tomography. Compared with the baseline log, wireline sonic log made 3 months later showed a weak and slower arrival of compressional wave over the perforated interval. Results from crosswell tomography data also showed changes in compressional velocity. Successful measurement of plume evolution documents an effective method to monitor CO2 in reservoirs and document migration.

Analytical and Biological Methods for Probing the Blood-Brain Barrier

PubMed Central

Sloan, Courtney D. Kuhnline; Nandi, Pradyot; Linz, Thomas H.; Aldrich, Jane V.; Audus, Kenneth L.; Lunte, Susan M.

2013-01-01

The blood-brain barrier (BBB) is an important interface between the peripheral and central nervous systems. It protects the brain against the infiltration of harmful substances and regulates the permeation of beneficial endogenous substances from the blood into the extracellular fluid of the brain. It can also present a major obstacle in the development of drugs that are targeted for the central nervous system. Several methods have been developed to investigate the transport and metabolism of drugs, peptides, and endogenous compounds at the BBB. In vivo methods include intravenous injection, brain perfusion, positron emission tomography, and microdialysis sampling. Researchers have also developed in vitro cell-culture models that can be employed to investigate transport and metabolism at the BBB without the complication of systemic involvement. All these methods require sensitive and selective analytical methods to monitor the transport and metabolism of the compounds of interest at the BBB. PMID:22708905

Intrastromal Delivery of Bevacizumab Using Microneedles to Treat Corneal Neovascularization

PubMed Central

Kim, Yoo C.; Grossniklaus, Hans E.; Edelhauser, Henry F.; Prausnitz, Mark R.

2014-01-01

Purpose. This study tested the hypothesis that highly targeted intrastromal delivery of bevacizumab using coated microneedles allows dramatic dose sparing compared with subconjunctival and topical delivery for treatment of corneal neovascularization. Methods. Stainless steel microneedles 400 μm in length were coated with bevacizumab. A silk suture was placed in the cornea approximately 1 mm from the limbus to induce corneal neovascularization in the eyes of New Zealand white rabbits that were divided into different groups: untreated, microneedle delivery, topical eye drop, and subconjunctival injection of bevacizumab. All drug treatments were initiated 4 days after suture placement and area of neovascularization was measured daily by digital photography for 18 days. Results. Eyes treated once with 4.4 μg bevacizumab using microneedles reduced neovascularization compared with untreated eyes by 44% (day 18). Eyes treated once with 2500 μg bevacizumab using subconjunctival injection gave similar results to microneedle-treated eyes. Eyes treated once with 4.4 μg subconjunctival bevacizumab showed no significant effect compared with untreated eyes. Eyes treated with 52,500 μg bevacizumab by eye drops three times per day for 14 days reduced the neovascularization area compared with untreated eyes by 6% (day 18), which was significantly less effective than the single microneedle treatment. Visual exam and histological analysis showed no observable effect of microneedle treatment on corneal transparency or microanatomical structure. Conclusions. This study shows that microneedles can target drug delivery to corneal stroma in a minimally invasive way and demonstrates effective suppression of corneal neovascularization after suture-induced injury using a much lower dose compared with conventional methods. PMID:25212779

Comparing respondent-driven sampling and targeted sampling methods of recruiting injection drug users in San Francisco.

PubMed

Kral, Alex H; Malekinejad, Mohsen; Vaudrey, Jason; Martinez, Alexis N; Lorvick, Jennifer; McFarland, Willi; Raymond, H Fisher

2010-09-01

The objective of this article is to compare demographic characteristics, risk behaviors, and service utilization among injection drug users (IDUs) recruited from two separate studies in San Francisco in 2005, one which used targeted sampling (TS) and the other which used respondent-driven sampling (RDS). IDUs were recruited using TS (n = 651) and RDS (n = 534) and participated in quantitative interviews that included demographic characteristics, risk behaviors, and service utilization. Prevalence estimates and 95% confidence intervals (CIs) were calculated to assess whether there were differences in these variables by sampling method. There was overlap in 95% CIs for all demographic variables except African American race (TS: 45%, 53%; RDS: 29%, 44%). Maps showed that the proportion of IDUs distributed across zip codes were similar for the TS and RDS sample, with the exception of a single zip code that was more represented in the TS sample. This zip code includes an isolated, predominantly African American neighborhood where only the TS study had a field site. Risk behavior estimates were similar for both TS and RDS samples, although self-reported hepatitis C infection was lower in the RDS sample. In terms of service utilization, more IDUs in the RDS sample reported no recent use of drug treatment and syringe exchange program services. Our study suggests that perhaps a hybrid sampling plan is best suited for recruiting IDUs in San Francisco, whereby the more intensive ethnographic and secondary analysis components of TS would aid in the planning of seed placement and field locations for RDS.

Single hole multi-parameter downhole monitoring of shallow CO2 injection at Maguelone experimental site (Languedoc, France)

NASA Astrophysics Data System (ADS)

Denchik, N.; Pezard, P. A.; Abdoulghafour, H.; Lofi, J.; Neyens, D.; Perroud, H.; Henry, G.; Rolland, B.

2015-12-01

The Maguelone experimental site for shallow subsurface hydrogeophysical monitoring, located along the Mediterranean Lido near Montpellier (Languedoc, France) has proven over the years to provide a unique setup to test gas storage monitoring methods at shallow depth. The presence of two small reservoirs (R1: 13-16 m and R2: 8-9 m) with impermeable boundaries provides an opportunity to study a saline formation for geological storage both in the field and in a laboratory context. This integrated monitoring concept was first applied at Maguelone for characterization of the reservoir state before and during N2 and CO2 injections as part of the MUSTANG FP7 project. Multimethod monitoring was shown to be sensitive to gas storage within a saline reservoir with clear data changes immediately after the beginning of injection. Pressure remains the first indicator of gas storage at ~8-9 m depth in a small permeable unit (gravels/shells) under the Holocene lagoonal sediments. A good correlation is also obtained between the resistivity response and geochemical parameters from pore fluid sampling (pH, minor and major cation concentrations) at this depth. On the basis of previous gas injection experiments, new holes were drilled as part of PANACEA (EC project) in 2014, including an injection hole targeted for injection at 8-9 m depth in the R2 reservoir in order to have gas injection and gas storage at the same depth, a single hole multi-parameter observatory, and a seismic source hole. A total volume of ~48 m3 of CO2 was injected over ~2 hours on December 4, 2014. The injection rate varied from 24 to 30 m3/h, with a well head pressure of 1.8 bars. All downhole monitoring technologies (resistivity, temperature, pressure, SP and seismic measurements) were combined in the single hole observatory. Such device allows monitoring the downhole system before and after injection and the gas migration from the injection hole, helping to characterize the transport mechanism. Decreasing the number of monitoring-measurements and verification (MMV) holes enables a significant decrease of gas leakage risk. This specific monitoring approach is expected to give information about the safety and reliability of CO2 storage operation that guarantees public acceptance.

Medroxyprogesterone Injection

MedlinePlus

... Medroxyprogesterone injection is a very effective method of birth control but does not prevent the spread of human ... you have been using a different method of birth control and are switching to medroxyprogesterone injection, your doctor ...

Gene silencing in Tribolium castaneum as a tool for the targeted identification of candidate RNAi targets in crop pests.

PubMed

Knorr, Eileen; Fishilevich, Elane; Tenbusch, Linda; Frey, Meghan L F; Rangasamy, Murugesan; Billion, Andre; Worden, Sarah E; Gandra, Premchand; Arora, Kanika; Lo, Wendy; Schulenberg, Greg; Valverde-Garcia, Pablo; Vilcinskas, Andreas; Narva, Kenneth E

2018-02-01

RNAi shows potential as an agricultural technology for insect control, yet, a relatively low number of robust lethal RNAi targets have been demonstrated to control insects of agricultural interest. In the current study, a selection of lethal RNAi target genes from the iBeetle (Tribolium castaneum) screen were used to demonstrate efficacy of orthologous targets in the economically important coleopteran pests Diabrotica virgifera virgifera and Meligethes aeneus. Transcript orthologs of 50 selected genes were analyzed in D. v. virgifera diet-based RNAi bioassays; 21 of these RNAi targets showed mortality and 36 showed growth inhibition. Low dose injection- and diet-based dsRNA assays in T. castaneum and D. v. virgifera, respectively, enabled the identification of the four highly potent RNAi target genes: Rop, dre4, ncm, and RpII140. Maize was genetically engineered to express dsRNA directed against these prioritized candidate target genes. T 0 plants expressing Rop, dre4, or RpII140 RNA hairpins showed protection from D. v. virgifera larval feeding damage. dsRNA targeting Rop, dre4, ncm, and RpII140 in M. aeneus also caused high levels of mortality both by injection and feeding. In summary, high throughput systems for model organisms can be successfully used to identify potent RNA targets for difficult-to-work with agricultural insect pests.

Treatment readiness, attitudes toward, and experiences with methadone and buprenorphine maintenance therapy among people who inject drugs in Malaysia

PubMed Central

Vijay, Aishwarya; Bazazi, Alexander R.; Yee, Ilias; Kamarulzaman, Adeeba; Altice, Frederick L.

2016-01-01

Background Little is known about attitudes toward and experiences with opioid maintenance therapy (OMT) among people who inject drugs in Malaysia, a country where people who inject drugs comprise 1.3% of the adult population. Methods In 2010, 460 people who inject drugs in Greater Kuala Lumpur, Malaysia were surveyed to evaluate attitudes toward and experience with OMT and treatment readiness. Attitudes towards OMT with both methadone and buprenorphine were assessed using an opinions scale. Multivariable linear regression was used to assess correlates of treatment readiness, measured with the 19-item Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Results All 460 participants used opioids and nearly all (99.1%) met criteria for opioid dependence. Few had had previous experience with methadone (9.3%) or buprenorphine (12.6%) maintenance therapy, yet many had used methadone (55.2%) or buprenorphine (51.7%) outside of treatment settings. Fifteen percent had injected buprenorphine in the past month, and of the few that were currently receiving buprenorphine maintenance therapy, almost all were injecting it. The majority of subjects exhibited a moderate level of treatment readiness and a preference for methadone over buprenorphine. Those with low treatment readiness scores were more likely to have previous experience with compulsory drug detention centers (p<0.01), needle/syringe exchange programs (p<0.005), or be of Indian ethnicity (p<0.001). Past use of methadone (p<0.01), older age (p<0.001), stress symptom severity (p<0.001), and sharing of needles or syringes (p<0.05) were associated with higher treatment readiness scores. Conclusion There are suboptimal levels of OMT experience among people who inject drugs that may be improved by addressing factors that influence patient attitudes. Those individuals with moderate treatment readiness may be targeted by brief motivational and cognitive interventions in primary care, prisons or OMT clinics aimed at improving entry into and retention in treatment. PMID:25841703

Systemic Injection of Neural Stem/Progenitor Cells in Mice with Chronic EAE

PubMed Central

Donegà, Matteo; Giusto, Elena; Cossetti, Chiara; Schaeffer, Julia; Pluchino, Stefano

2014-01-01

Neural stem/precursor cells (NPCs) are a promising stem cell source for transplantation approaches aiming at brain repair or restoration in regenerative neurology. This directive has arisen from the extensive evidence that brain repair is achieved after focal or systemic NPC transplantation in several preclinical models of neurological diseases. These experimental data have identified the cell delivery route as one of the main hurdles of restorative stem cell therapies for brain diseases that requires urgent assessment. Intraparenchymal stem cell grafting represents a logical approach to those pathologies characterized by isolated and accessible brain lesions such as spinal cord injuries and Parkinson's disease. Unfortunately, this principle is poorly applicable to conditions characterized by a multifocal, inflammatory and disseminated (both in time and space) nature, including multiple sclerosis (MS). As such, brain targeting by systemic NPC delivery has become a low invasive and therapeutically efficacious protocol to deliver cells to the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system (CNS). This alternative method of cell delivery relies on the NPC pathotropism, specifically their innate capacity to (i) sense the environment via functional cell adhesion molecules and inflammatory cytokine and chemokine receptors; (ii) cross the leaking anatomical barriers after intravenous (i.v.) or intracerebroventricular (i.c.v.) injection; (iii) accumulate at the level of multiple perivascular site(s) of inflammatory brain and spinal cord damage; and (i.v.) exert remarkable tissue trophic and immune regulatory effects onto different host target cells in vivo. Here we describe the methods that we have developed for the i.v. and i.c.v. delivery of syngeneic NPCs in mice with experimental autoimmune encephalomyelitis (EAE), as model of chronic CNS inflammatory demyelination, and envisage the systemic stem cell delivery as a valuable technique for the selective targeting of the inflamed brain in regenerative neurology. PMID:24798882

Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel.

PubMed

Kim, Yusung; Seol, Dong Rim; Mohapatra, Sucheta; Sunderland, John J; Schultz, Michael K; Domann, Frederick E; Lim, Tae-Hong

2014-04-01

To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor are promising. Published by Elsevier Inc.

Demonstration of self-truncated ionization injection for GeV electron beams

PubMed Central

Mirzaie, M.; Li, S.; Zeng, M.; Hafz, N. A. M.; Chen, M.; Li, G. Y.; Zhu, Q. J.; Liao, H.; Sokollik, T.; Liu, F.; Ma, Y. Y.; Chen, L.M.; Sheng, Z. M.; Zhang, J.

2015-01-01

Ionization-induced injection mechanism was introduced in 2010 to reduce the laser intensity threshold for controllable electron trapping in laser wakefield accelerators (LWFA). However, usually it generates electron beams with continuous energy spectra. Subsequently, a dual-stage target separating the injection and acceleration processes was regarded as essential to achieve narrow energy-spread electron beams by ionization injection. Recently, we numerically proposed a self-truncation scenario of the ionization injection process based upon overshooting of the laser-focusing in plasma which can reduce the electron injection length down to a few hundred micrometers, leading to accelerated beams with extremely low energy-spread in a single-stage. Here, using 100 TW-class laser pulses we report experimental observations of this injection scenario in centimeter-long plasma leading to the generation of narrow energy-spread GeV electron beams, demonstrating its robustness and scalability. Compared with the self-injection and dual-stage schemes, the self-truncated ionization injection generates higher-quality electron beams at lower intensities and densities, and is therefore promising for practical applications. PMID:26423136

Calculation method of water injection forward modeling and inversion process in oilfield water injection network

NASA Astrophysics Data System (ADS)

Liu, Long; Liu, Wei

2018-04-01

A forward modeling and inversion algorithm is adopted in order to determine the water injection plan in the oilfield water injection network. The main idea of the algorithm is shown as follows: firstly, the oilfield water injection network is inversely calculated. The pumping station demand flow is calculated. Then, forward modeling calculation is carried out for judging whether all water injection wells meet the requirements of injection allocation or not. If all water injection wells meet the requirements of injection allocation, calculation is stopped, otherwise the demand injection allocation flow rate of certain step size is reduced aiming at water injection wells which do not meet requirements, and next iterative operation is started. It is not necessary to list the algorithm into water injection network system algorithm, which can be realized easily. Iterative method is used, which is suitable for computer programming. Experimental result shows that the algorithm is fast and accurate.

Neurokinin B-producing projection neurons in the lateral stripe of the striatum and cell clusters of the accumbens nucleus in the rat.

PubMed

Zhou, Ligang; Furuta, Takahiro; Kaneko, Takeshi

2004-12-06

Neurons producing preprotachykinin B (PPTB), the precursor of neurokinin B, constitute 5% of neurons in the dorsal striatum and project to the substantia innominata (SI) selectively. In the ventral striatum, PPTB-producing neurons are collected mainly in the lateral stripe of the striatum (LSS) and cell clusters of the accumbens nucleus (Acb). In the present study, we first examined the distribution of PPTB-immunoreactive neurons in rat ventral striatum and found that a large part of the PPTB-immunoreactive cell clusters was continuous to the LSS, but a smaller part was not. Thus, we divided the PPTB-immunoreactive cell clusters into the LSS-associated and non-LSS-associated ones. We next investigated the projection targets of the PPTB-producing ventral striatal neurons by combining immunofluorescence labeling and retrograde tracing. After injection of Fluoro-Gold into the basal component of the SI (SIb) and medial part of the interstitial nucleus of posterior limb of the anterior commissure, many PPTB-immunoreactive neurons were retrogradely labeled in the LSS-associated cell clusters and LSS, respectively. When the injection site included the ventral part of the sublenticular component of the SI(SIsl), retrogradely labeled neurons showed PPTB-immunoreactivity frequently in non-LSS-associated cell clusters. Furthermore, these PPTB-immunoreactive projections were confirmed by the double-fluorescence method after anterograde tracer injection into the ventral striatum containing the cell clusters. Since the dorsalmost part of the SIsl is known to receive strong inputs from PPTB-producing dorsal striatal neurons, the present results indicate that PPTB-producing ventral striatal neurons project to basal forebrain target regions in parallel with dorsal striatal neurons without significant convergence. 2004 Wiley-Liss, Inc.

Deformational injection rate measuring method

NASA Astrophysics Data System (ADS)

Marčič, Milan

2002-09-01

After completing the diesel engine endurance testing, we detected various traces of thermal load on the walls of combustion chambers located in the engine pistons. The engines were fitted with ω combustion chambers. The thermal load of different intensity levels occurred where the spray of fuel, fuel vapor, and air interacted with the combustion chamber wall. The uneven thermal load distribution of the combustion chamber wall results from varying injection rates in each injection nozzle hole. The most widely applied controlling methods so far for injection rate measurement, such as the Zeuch and Bosch concepts, allow measurement of only the total injection rate in multihole nozzles, without providing any indication whatsoever of the injection rate differences in individual injection nozzle holes. The new deformational measuring method described in the article allows the injection rate to be measured in each hole of the multihole nozzle. The results of the measurements using this method showed that the differences occurred in injection rates of individual injection nozzle holes. These differences may be the cause of various thermal loads on the combustion chamber walls. The criterion for injection rate is the deformation of the membrane due to an increase in the fuel quantity in the measuring space and due to the pressure waves resulting from the fuel being injected into the measuring space. The membrane deformation is measured using strain gauges, glued to the membrane and forming the Wheatstone's bridge. We devoted special attention to the temperature compensation of the Wheatstone's bridge and the membrane, heated up during the measurements.

Wallula Basalt Pilot Demonstration Project: Post-injection Results and Conclusions

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGrail, Bernard Pete; Schaef, Herbert T.; Spane, Frank A.

Deep underground geologic formations are emerging as a reasonable option for long-term storage of CO 2, including large continental flood basalt formations. At the GHGT-11 and GHGT-12 conferences, progress was reported on the initial phases for Wallula Basalt Pilot demonstration test (located in Eastern Washington state), where nearly 1,000 metric tons of CO 2 were injected over a 3-week period during July/August 2013. The target CO 2 injection intervals were two permeable basalt interflow reservoir zones with a combined thickness of ~20 m that occur within a layered basalt sequence between a depth of 830-890 m below ground surface. Duringmore » the two-year post-injection period, downhole fluid samples were periodically collected during this post-injection monitoring phase, coupled with limited wireline borehole logging surveys that provided indirect evidence of on-going chemical geochemical reactions/alterations and CO 2 disposition. A final detailed post-closure field characterization program that included downhole fluid sampling, and performance of hydrologic tests and wireline geophysical surveys. Included as part of the final wireline characterization activities was the retrieval of side-wall cores from within the targeted injection zones. These cores were examined for evidence of in-situ mineral carbonization. Visual observations of the core material identified small globular nodules, translucent to yellow in color, residing within vugs and small cavities of the recovered basalt side-wall cores, which were not evident in pre-injection side-wall cores obtained from the native basalt formation. Characterization by x-ray diffraction identified these nodular precipitates as ankerite, a commonly occurring iron and calcium rich carbonate. Isotopic characterization (δ 13C, δ 18O) conducted on the ankerite nodules indicate a distinct isotopic signature that is closely aligned with that of the injected CO 2. Both the secondary mineral nodules and injected CO 2 are measurably different from the isotopic content of basalt, injection zone groundwater and for naturally occurring calcite. Final post-injection wireline geophysical logging results also indicate the presence of free-phase CO 2 at the top of the two injection interflow zones, with no vertical migration of CO 2 above the injection horizons. Furthermore, these findings are significant and demonstrate the feasibility of sequestering CO 2 in a basalt formation.« less

Wallula Basalt Pilot Demonstration Project: Post-injection Results and Conclusions

DOE PAGES

McGrail, Bernard Pete; Schaef, Herbert T.; Spane, Frank A.; ...

2017-08-18

Deep underground geologic formations are emerging as a reasonable option for long-term storage of CO 2, including large continental flood basalt formations. At the GHGT-11 and GHGT-12 conferences, progress was reported on the initial phases for Wallula Basalt Pilot demonstration test (located in Eastern Washington state), where nearly 1,000 metric tons of CO 2 were injected over a 3-week period during July/August 2013. The target CO 2 injection intervals were two permeable basalt interflow reservoir zones with a combined thickness of ~20 m that occur within a layered basalt sequence between a depth of 830-890 m below ground surface. Duringmore » the two-year post-injection period, downhole fluid samples were periodically collected during this post-injection monitoring phase, coupled with limited wireline borehole logging surveys that provided indirect evidence of on-going chemical geochemical reactions/alterations and CO 2 disposition. A final detailed post-closure field characterization program that included downhole fluid sampling, and performance of hydrologic tests and wireline geophysical surveys. Included as part of the final wireline characterization activities was the retrieval of side-wall cores from within the targeted injection zones. These cores were examined for evidence of in-situ mineral carbonization. Visual observations of the core material identified small globular nodules, translucent to yellow in color, residing within vugs and small cavities of the recovered basalt side-wall cores, which were not evident in pre-injection side-wall cores obtained from the native basalt formation. Characterization by x-ray diffraction identified these nodular precipitates as ankerite, a commonly occurring iron and calcium rich carbonate. Isotopic characterization (δ 13C, δ 18O) conducted on the ankerite nodules indicate a distinct isotopic signature that is closely aligned with that of the injected CO 2. Both the secondary mineral nodules and injected CO 2 are measurably different from the isotopic content of basalt, injection zone groundwater and for naturally occurring calcite. Final post-injection wireline geophysical logging results also indicate the presence of free-phase CO 2 at the top of the two injection interflow zones, with no vertical migration of CO 2 above the injection horizons. Furthermore, these findings are significant and demonstrate the feasibility of sequestering CO 2 in a basalt formation.« less

Phage-display library biopanning and bioinformatic analysis yielded a high-affinity peptide to inflamed vascular endothelium both in vitro and in vivo.

PubMed

Yang, Min; Liu, Chenwu; Niu, Maochang; Hu, Yonghe; Guo, Mingyang; Zhang, Jun; Luo, Yong; Yuan, Weili; Yang, Mei; Yun, Mingdong; Guo, Linling; Yan, Jiao; Liu, Defang; Liu, Jinghua; Jiang, Yong

2014-01-28

Vascular inflammation is considered the primary pathological condition occurring in many chronic diseases. To detect the inflamed endothelium via imaging analysis or guide the drug to target lesions is therefore important for early diagnosis and treatment of vascular inflammatory diseases. In this study, we obtained a novel peptide NTTTH through high throughout biopanning and bioinformatic analysis. In vitro studies indicated that NTTTH homologs could especially target inflamed vascular endothelial cells, as imaging quantitative analysis indicated that the mean of integrated optical density (MIOD) and mean of stained area (MSA) were significantly higher versus control (P<0.05). In vivo studies showed that, after intravenous injection of enhanced green fluorescent protein (EGFP)-labeled NTTTH homologs into the lipopolysaccharide (LPS)-inflamed mice for 30min, NTTTH homologs were distributed in highly vascularized and inflamed organs like liver and kidney. As a control, little fluorescence could be detected in mice injected with EGFP alone. Cryosection showed that NTTTH homologs especially targeted inflamed vasculatures but not normal ones. We did not detect fluorescence signal in either normal or inflamed mice which were injected with EGFP alone. The results suggested the role of NTTTH homologs in guiding the targeted binding of EGFP to inflamed vasculature and the potential usage for imaging detection and drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Synergistic effects of dendritic cell targeting and laser-microporation on enhancing epicutaneous skin vaccination efficacy.

PubMed

Machado, Yoan; Duinkerken, Sanne; Hoepflinger, Veronika; Mayr, Melissa; Korotchenko, Evgeniia; Kurtaj, Almedina; Pablos, Isabel; Steiner, Markus; Stoecklinger, Angelika; Lübbers, Joyce; Schmid, Maximillian; Ritter, Uwe; Scheiblhofer, Sandra; Ablinger, Michael; Wally, Verena; Hochmann, Sarah; Raninger, Anna M; Strunk, Dirk; van Kooyk, Yvette; Thalhamer, Josef; Weiss, Richard

2017-11-28

Due to its unique immunological properties, the skin is an attractive target tissue for allergen-specific immunotherapy. In our current work, we combined a dendritic cell targeting approach with epicutaneous immunization using an ablative fractional laser to generate defined micropores in the upper layers of the skin. By coupling the major birch pollen allergen Bet v 1 to mannan from S. cerevisiae via mild periodate oxidation we generated hypoallergenic Bet-mannan neoglycoconjugates, which efficiently targeted CD14 + dendritic cells and Langerhans cells in human skin explants. Mannan conjugation resulted in sustained release from the skin and retention in secondary lymphoid organs, whereas unconjugated antigen showed fast renal clearance. In a mouse model, Bet-mannan neoglycoconjugates applied via laser-microporated skin synergistically elicited potent humoral and cellular immune responses, superior to intradermal injection. The induced antibody responses displayed IgE-blocking capacity, highlighting the therapeutic potential of the approach. Moreover, application via micropores, but not by intradermal injection, resulted in a mixed TH1/TH17-biased immune response. Our data clearly show that applying mannan-neoglycoconjugates to an organ rich in dendritic cells using laser-microporation is superior to intradermal injection. Due to their low IgE binding capacity and biodegradability, mannan neoglycoconjugates therefore represent an attractive formulation for allergen-specific epicutaneous immunotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of injection practice in primary health care facilities of Shiraz, Iran.

PubMed

Mclaws, Mary-Louise; Ghahramani, Sulmaz; Palenik, Charles John; Keshtkar, Vahid; Askarian, Mehrdad

2014-03-01

Occupational risk for several bloodborne viruses is attributable to unsafe injection practices. To understand injection frequency and safety, we surveyed injection rates and factors influencing injection prescription in primary health care facilities and associated health clinics in Shiraz, Iran. We used both quantitative and qualitative approaches to study the frequency and safety of injections delivered in 27 primary health care facilities. We used observations and 3 data collecting tools. Patterns of 600 general practice physicians' (GPs) prescriptions were also reviewed. In-depth interviews to elicit the factors contributing to injection prescriptions were conducted. The annual per capita injection rate was 3.12. Corticosteroids were prescribed more frequently than antibiotics (P < .001). Knowledge of participants concerning transmission risks for 3 of the most common bloodborne infections (BBIs) was less than 75%. Factors affecting use of injections by GPs included strong patient preference for injections over oral medications and financial benefit for GPs, especially those in private practice settings. Frequency of therapeutic injections in the participating facilities in Shiraz was high. Sociocultural factors in the patient community and their beliefs in the effectiveness of injections exerted influence on GP prescribing practices. Programs for appropriate and safe injection practices should target GP and injection providers, as well as patients, informing them about alternative treatments and possible complications of unnecessary and unsafe injections. Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. All rights reserved.

Status of the laser ion source at IMP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sha, S.; Graduate University of Chinese Academy of Sciences, Beijing 100049; School of Nuclear science and technology, Lanzhou University, Lanzhou 73000

2012-02-15

A laser (Nd:YAG laser, 3 J, 1064 nm, 8-10 ns) ion source has been built and under development at IMP to provide pulsed high-charge-state heavy ion beams to a radio frequency quadrupole (RFQ) for upgrading the IMP accelerators with a new low-energy beam injector. The laser ion source currently operates in a direct plasma injection scheme to inject the high charge state ions produced from a solid target into the RFQ. The maximum power density on the target was about 8.4 x 10{sup 12} W/cm{sup 2}. The preliminary experimental results will be presented and discussed in this paper.

Microstructured Surface Arrays for Injection of Zebrafish Larvae

PubMed Central

Irimia, Daniel

2017-01-01

Abstract Microinjection of zebrafish larvae is an essential technique for delivery of treatments, dyes, microbes, and xenotransplantation into various tissues. Although a number of casts are available to orient embryos at the single-cell stage, no device has been specifically designed to position hatching-stage larvae for microinjection of different tissues. In this study, we present a reusable silicone device consisting of arrayed microstructures, designed to immobilize 2 days postfertilization larvae in lateral, ventral, and dorsal orientations, while providing maximal access to target sites for microinjection. Injection of rhodamine dextran was used to demonstrate the utility of this device for precise microinjection of multiple anatomical targets. PMID:28151697

A Multifunctional Mesothelin Antibody-tagged Microparticle Targets Human Mesotheliomas

PubMed Central

Macura, Sherrill L.; Hillegass, Jedd M.; Steinbacher, Jeremy L.; MacPherson, Maximilian B.; Shukla, Arti; Beuschel, Stacie L.; Perkins, Timothy N.; Butnor, Kelly J.; Lathrop, Melissa J.; Sayan, Mutlay; Hekmatyar, Khan; Taatjes, Douglas J.; Kauppinen, Risto A.; Landry, Christopher C.

2012-01-01

Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin. PMID:22723527

The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth: Different administration routes.

PubMed

Fasehee, Hamidreza; Zarrinrad, Ghazaleh; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamidollah; Faghihi, Shahab

2016-06-01

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

A novel, volumizing cosmetic formulation significantly improves the appearance of target Glabellar lines, nasolabial folds, and crow's feet in a double-blind, vehicle-controlled clinical trial.

PubMed

Farris, Patricia K; Edison, Brenda L; Weinkauf, Ronni L; Green, Barbara A

2014-01-01

Facial lines and wrinkles are caused by many factors including constant exposure to external elements, such as UV rays, as well as the dynamic nature of facial expression. Many cosmetic products and procedures provide global improvement to aging skin, whereas injectable therapies are frequently utilized to diminish specific, target wrinkles. Despite their broad availability, some patients are unwilling to undergo injectables and would benefit from an effective topical option. A noninvasive option to volumize target wrinkle areas could also extend benefits of commonly used cosmetic anti-aging products. To this end, a two-step formulation containing the novel, cosmetic anti-aging ingredient, N-acetyl tyrosinamide, was developed for use on targeted wrinkle areas. The tolerability and efficacy of the serum plus cream were tested for 16 weeks in women with moderate facial photodamage on predetermined wrinkle areas (glabellar lines, nasolabial folds, under eye lines, and lateral canthal (crow's feet) wrinkles) in a single-center, randomized, double-blind, vehicle-controlled, clinical trial. Seventy women (47 Active group, 23 Vehicle group) completed the study. Digital photography, clinical grading, ultrasound and self-assessment scores confirmed improvement to wrinkle areas. The topical cosmetic formulation was statistically superior (P<0.05) to its vehicle in visually improving nasolabial folds, glabellar lines, crow's feet, and under eye wrinkles and in reducing pinch recoil time. Both the test formulation and its vehicle were tolerated well. The novel, two-step cosmetic formulation reduced the appearance of wrinkles and increased skin elasticity thus providing an effective anti-aging option for target wrinkle areas. This study suggests that in addition to its use as monotherapy for reducing targeted lines and wrinkles this cosmetic formulation may be also serve as an adjuvant to injectable therapies.

Trends in the Cost and Use of Targeted Cancer Therapies for the Privately Insured Nonelderly: 2001 to 2011

PubMed Central

Shih, Ya-Chen Tina; Smieliauskas, Fabrice; Geynisman, Daniel M.; Kelly, Ronan J.; Smith, Thomas J.

2015-01-01

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment. PMID:25987701

Utility of Vibratory Stimulation for Reducing Intraoral Injection Pain.

PubMed

Erdogan, Ozgur; Sinsawat, Anatachai; Pawa, Sudeep; Rintanalert, Duangtawan; Vuddhakanok, Suchada

2018-01-01

Intraoral local anesthesia injection is often perceived as a painful and anxiety-causing dental procedure. Vibration stimulus is one of the nonpharmacologic methods used to reduce unwanted sensations of local anesthesia injection. This clinical study evaluated the effectiveness of a recently introduced vibratory stimulation device in intraoral local anesthesia administration. Thirty-two subjects underwent 2 maxillary local anesthesia injections in 2 different sessions: 1 with conventional techniques and 1 with the aid of a vibratory stimulation device (DentalVibe). The pain levels were evaluated with a visual analog scale and the Wong-Baker FACES Pain Rating Scale. The subjects were asked to choose the preferred method for future injections. The data were evaluated statistically. There were no significant differences between the 2 injection methods with regard to either pain evaluation method. The preference of the subjects regarding future injection technique was evenly distributed between the groups. The vibratory stimulation device used in this study did not provide any reduction in pain level associated with maxillary infiltration local anesthesia administration.

Cerebellar inactivation impairs memory of learned prism gaze-reach calibrations.

PubMed

Norris, Scott A; Hathaway, Emily N; Taylor, Jordan A; Thach, W Thomas

2011-05-01

Three monkeys performed a visually guided reach-touch task with and without laterally displacing prisms. The prisms offset the normally aligned gaze/reach and subsequent touch. Naive monkeys showed adaptation, such that on repeated prism trials the gaze-reach angle widened and touches hit nearer the target. On the first subsequent no-prism trial the monkeys exhibited an aftereffect, such that the widened gaze-reach angle persisted and touches missed the target in the direction opposite that of initial prism-induced error. After 20-30 days of training, monkeys showed long-term learning and storage of the prism gaze-reach calibration: they switched between prism and no-prism and touched the target on the first trials without adaptation or aftereffect. Injections of lidocaine into posterolateral cerebellar cortex or muscimol or lidocaine into dentate nucleus temporarily inactivated these structures. Immediately after injections into cortex or dentate, reaches were displaced in the direction of prism-displaced gaze, but no-prism reaches were relatively unimpaired. There was little or no adaptation on the day of injection. On days after injection, there was no adaptation and both prism and no-prism reaches were horizontally, and often vertically, displaced. A single permanent lesion (kainic acid) in the lateral dentate nucleus of one monkey immediately impaired only the learned prism gaze-reach calibration and in subsequent days disrupted both learning and performance. This effect persisted for the 18 days of observation, with little or no adaptation.

Cerebellar inactivation impairs memory of learned prism gaze-reach calibrations

PubMed Central

Hathaway, Emily N.; Taylor, Jordan A.; Thach, W. Thomas

2011-01-01

Three monkeys performed a visually guided reach-touch task with and without laterally displacing prisms. The prisms offset the normally aligned gaze/reach and subsequent touch. Naive monkeys showed adaptation, such that on repeated prism trials the gaze-reach angle widened and touches hit nearer the target. On the first subsequent no-prism trial the monkeys exhibited an aftereffect, such that the widened gaze-reach angle persisted and touches missed the target in the direction opposite that of initial prism-induced error. After 20–30 days of training, monkeys showed long-term learning and storage of the prism gaze-reach calibration: they switched between prism and no-prism and touched the target on the first trials without adaptation or aftereffect. Injections of lidocaine into posterolateral cerebellar cortex or muscimol or lidocaine into dentate nucleus temporarily inactivated these structures. Immediately after injections into cortex or dentate, reaches were displaced in the direction of prism-displaced gaze, but no-prism reaches were relatively unimpaired. There was little or no adaptation on the day of injection. On days after injection, there was no adaptation and both prism and no-prism reaches were horizontally, and often vertically, displaced. A single permanent lesion (kainic acid) in the lateral dentate nucleus of one monkey immediately impaired only the learned prism gaze-reach calibration and in subsequent days disrupted both learning and performance. This effect persisted for the 18 days of observation, with little or no adaptation. PMID:21389311

Characterization of intravitreally delivered capsid mutant AAV2-Cre vector to induce tissue-specific mutations in murine retinal ganglion cells.

PubMed

Langouet-Astrie, Christophe J; Yang, Zhiyong; Polisetti, Sraavya M; Welsbie, Derek S; Hauswirth, William W; Zack, Donald J; Merbs, Shannath L; Enke, Raymond A

2016-10-01

Targeted expression of Cre recombinase in murine retinal ganglion cells (RGCs) by viral vector is an effective strategy for creating tissue-specific gene knockouts for investigation of genetic contribution to RGC degeneration associated with optic neuropathies. Here we characterize dosage, efficacy and toxicity for sufficient intravitreal delivery of a capsid mutant Adeno-associated virus 2 (AAV2) vector encoding Cre recombinase. Wild type and Rosa26 (R26) LacZ mice were intravitreally injected with capsid mutant AAV2 viral vectors. Murine eyes were harvested at intervals ranging from 2 weeks to 15 weeks post-injection and were assayed for viral transduction, transgene expression and RGC survival. 10(9) vector genomes (vg) were sufficient for effective in vivo targeting of murine ganglion cell layer (GCL) retinal neurons. Transgene expression was observed as early as 2 weeks post-injection of viral vectors and persisted to 11 weeks. Early expression of Cre had no significant effect on RGC survival, while significant RGC loss was detected beginning 5 weeks post-injection. Early expression of viral Cre recombinase was robust, well-tolerated and predominantly found in GCL neurons suggesting this strategy can be effective in short-term RGC-specific mutation studies in experimental glaucoma models such as optic nerve crush and transection experiments. RGC degeneration with Cre expression for more than 4 weeks suggests that Cre toxicity is a limiting factor for targeted mutation strategies in RGCs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Overview of Progress on the LANSCE Accelerator and Target Facilities Improvement Program

NASA Astrophysics Data System (ADS)

Macek, R. J.; Brun, T.; Donahue, J. B.; Fitzgerald, D. H.

1997-05-01

Three projects to improve the performance of the accelerator and target facilities for the Los Alamos Neutron Science Center have been initiated since 1994. The LANSCE Reliability Improvement Project was separated into two phases. Phase I, completed in 1995, was targeted at near-term improvements to beam availability that could be completed in a year. Phase II, now underway, consists of two projects: 1) converting the beam injection into the Proton Storage Ring (PSR) from the present two-step process H^- to H^0 to H^+) to direct injection of H^- beam in one step (H^- to H^+), and 2) an upgrade of the spallation neutron production target which will reduce the target change-out time from about a year to about three weeks. The third project, the SPSS Enhancement Project, is aimed at increasing the PSR output beam current from the present 70 μA at 20 Hz to 200 μA at 30 Hz, plus implementing seven new neutron scattering instruments. Objectives, plans, results and progress to date will be summarized.

Triple Therapy of HER2+ Cancer Using Radiolabeled Multifunctional Iron Oxide Nanoparticles and Alternating Magnetic Field.

PubMed

Zolata, Hamidreza; Afarideh, Hossein; Davani, Fereydoun Abbasi

2016-11-01

By using radio-labeled multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) and an alternating magnetic field (AMF), we carried out targeted hyperthermia, drug delivery, radio-immunotherapy (RIT), and controlled chemotherapy of cancer tumors. We synthesized and characterized Indium-111-labeled, Trastuzumab and Doxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs in our previous work. Then, we evaluated their capability in SPECT/MRI (single photon emission computed tomography/magnetic resonance imaging) dual modal molecular imaging, targeting, and controlled release. In this research, AMF was introduced to evaluate therapeutic effects of magnetic hyperthermia on radionuclide-chemo therapy of HER2 + cells and tumor (HER2 + )-bearing mice. In vitro and in vivo experiments using synthesized complex were repeated under an AMF (f: 100 KHz, H: 280 Gs). Instead of an intra-tumor injection in most hyperthermia experiments, SPIONs were injected to the tail vein, based on our delivery strategies. For magnetic delivery, we held a permanent Nd-B-Fe magnet near the tumor region. The results showed that simultaneous magnetic hyperthermia enhanced SKBR3 cancer cells, killing by 24%, 28%, 33%, and 80% at 48 hours post-treatment for treated cells with (1) bare SPIONs; (2) antibody-conjugated, DOX-free, surface-modified SPIONs; (3) 111 In-labeled, antibody-conjugated surface-modified SPIONs; and (4) 111 In-labeled, antibody- and DOX-conjugated surface-modified SPIONs, respectively. Moreover, tumor volume inhibitory rate was 85% after a 28 day period of treatment. By using this method, multimodal imaging-guided, targeted hyperthermia, RIT, and controlled chemotherapy could be achievable in the near future.

Correlation between positron emission tomography and Cerenkov luminescence imaging in vivo and ex vivo using 64Cu-labeled antibodies in a neuroblastoma mouse model.

PubMed

Maier, Florian C; Schmitt, Julia; Maurer, Andreas; Ehrlichmann, Walter; Reischl, Gerald; Nikolaou, Konstantin; Handgretinger, Rupert; Pichler, Bernd J; Thaiss, Wolfgang M

2016-10-11

Antibody-based therapies gain momentum in clinical therapy, thus the need for accurate imaging modalities with respect to target identification and therapy monitoring are of increasing relevance. Cerenkov luminescence imaging (CLI) are a novel method detecting charged particles emitted during radioactive decay with optical imaging. Here, we compare Position Emission Tomography (PET) with CLI in a multimodal imaging study aiming at the fast and efficient screening of monoclonal antibodies (mAb) designated for targeting of the neuroblastoma-characteristic epitope disialoganglioside GD2. Neuroblastoma-bearing SHO mice were injected with a 64Cu-labeled GD2-specific mAb. The tumor uptake was imaged 3 h, 24 h and 48 h after tracer injection with both, PET and CLI, and was compared to the accumulation in GD2-negative control tumors (human embryonic kidney, HEK-293). In addition to an in vivo PET/CLI-correlation over time, we also demonstrate linear correlations of CLI- and γ-counter-based biodistribution analysis. CLI with its comparably short acquisition time can thus be used as an attractive one-stop-shop modality for the longitudinal monitoring of antibody-based tumor targeting and ex vivo biodistribution.These findings suggest CLI as a reliable alternative for PET and biodistribution studies with respect to fast and high-throughput screenings in subcutaneous tumors traced with radiolabeled antibodies. However, in contrast to PET, CLI is not limited to positron-emitting isotopes and can therefore also be used for the visualization of mAb labeled with therapeutic isotopes like electron emitters.

In vivo fluorescence lifetime imaging for monitoring the efficacy of the cancer treatment.

PubMed

Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Zielinski, Rafal; Capala, Jacek; Gandjbakhche, Amir

2014-07-01

Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size. Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (∼0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns. The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. ©2014 American Association for Cancer Research.

In-vivo fluorescence lifetime imaging for monitoring the efficacy of the cancer treatment

PubMed Central

Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Zielinski, Rafal; Capala, Jacek; Gandjbakhche, Amir

2015-01-01

Purpose Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in-vivo fluorescence lifetime imaging with HER2 targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. Experimental Design HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice, bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pre-treatment size. Results Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (~0.13ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment) the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03ns. Conclusions The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in-vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. PMID:24671949

A novel high-throughput method for supported liquid extraction of retinol and alpha-tocopherol from human serum and simultaneous quantitation by liquid chromatography tandem mass spectrometry.

PubMed

Hinchliffe, Edward; Rudge, James; Reed, Paul

2016-07-01

Measurement of vitamin A (retinol) and E (alpha-tocopherol) in UK clinical laboratories is currently performed exclusively by high-performance liquid chromatography with ultraviolet detection. We investigated whether retinol and alpha-tocopherol could be measured simultaneously by liquid chromatography tandem mass spectrometry. Serum samples (100 μL) were extracted using Isolute + Supported Liquid Extraction plates. Chromatography was performed on a Phenomenex Kinetex Biphenyl 2.6 μm, 50 × 2.1 mm column, and liquid chromatography tandem mass spectrometry on a Waters Acquity TQD. Injection-to-injection time was 4.3 min. The assay was validated according to published guidelines. Patient samples were used to compare liquid chromatography tandem mass spectrometry and high-performance liquid chromatography with ultraviolet detection methods. For retinol and alpha-tocopherol, respectively, the assay was linear up to 6.0 and 80.0 μmol/L, and lower limit of quantification was 0.07 and 0.26 μmol/L. Intra and interassay imprecision were within desirable analytical specifications. Analysis of quality control material aligned to NIST SRM 968e, and relative spiked recovery from human serum, both yielded results within 15% of target values. Method comparison with high-performance liquid chromatography with ultraviolet detection methodology demonstrated a negative bias for retinol and alpha-tocopherol by the liquid chromatography tandem mass spectrometry method. Analysis of United Kingdom National External Quality Assurance Scheme samples yielded mean bias from the target value of +3.0% for retinol and -11.2% for alpha-tocopherol. We have developed a novel, high-throughput method for extraction of retinol and alpha-tocopherol from human serum followed by simultaneous quantitation by liquid chromatography tandem mass spectrometry. The method offers a rapid, sensitive, specific and cost-effective alternative to high-performance liquid chromatography with ultraviolet detection methodology, and is suitable for routine clinical monitoring of patients predisposed to fat-soluble vitamin malabsorption. © The Author(s) 2015.

Deformable registration for image-guided spine surgery: preserving rigid body vertebral morphology in free-form transformations

NASA Astrophysics Data System (ADS)

Reaungamornrat, S.; Wang, A. S.; Uneri, A.; Otake, Y.; Zhao, Z.; Khanna, A. J.; Siewerdsen, J. H.

2014-03-01

Purpose: Deformable registration of preoperative and intraoperative images facilitates accurate localization of target and critical anatomy in image-guided spine surgery. However, conventional deformable registration fails to preserve the morphology of rigid bone anatomy and can impart distortions that confound high-precision intervention. We propose a constrained registration method that preserves rigid morphology while allowing deformation of surrounding soft tissues. Method: The registration method aligns preoperative 3D CT to intraoperative cone-beam CT (CBCT) using free-form deformation (FFD) with penalties on rigid body motion imposed according to a simple intensity threshold. The penalties enforced 3 properties of a rigid transformation - namely, constraints on affinity (AC), orthogonality (OC), and properness (PC). The method also incorporated an injectivity constraint (IC) to preserve topology. Physical experiments (involving phantoms, an ovine spine, and a human cadaver) as well as digital simulations were performed to evaluate the sensitivity to registration parameters, preservation of rigid body morphology, and overall registration accuracy of constrained FFD in comparison to conventional unconstrained FFD (denoted uFFD) and Demons registration. Result: FFD with orthogonality and injectivity constraints (denoted FFD+OC+IC) demonstrated improved performance compared to uFFD and Demons. Affinity and properness constraints offered little or no additional improvement. The FFD+OC+IC method preserved rigid body morphology at near-ideal values of zero dilatation (D = 0.05, compared to 0.39 and 0.56 for uFFD and Demons, respectively) and shear (S = 0.08, compared to 0.36 and 0.44 for uFFD and Demons, respectively). Target registration error (TRE) was similarly improved for FFD+OC+IC (0.7 mm), compared to 1.4 and 1.8 mm for uFFD and Demons. Results were validated in human cadaver studies using CT and CBCT images, with FFD+OC+IC providing excellent preservation of rigid morphology and equivalent or improved TRE. Conclusions: A promising method for deformable registration in CBCT-guided spine surgery has been identified incorporating a constrained FFD to preserve bone morphology. The approach overcomes distortions intrinsic to unconstrained FFD and could better facilitate high-precision image-guided spine surgery.

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

PubMed Central

Vandergriff, Adam; Huang, Ke; Shen, Deliang; Hu, Shiqi; Hensley, Michael Taylor; Caranasos, Thomas G.; Qian, Li; Cheng, Ke

2018-01-01

Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart. Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis. Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes. Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis. PMID:29556361

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα.

PubMed

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-08-31

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer.

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα

PubMed Central

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-01-01

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer. PMID:27576898

Retrospective Cost Adaptive Control with Concurrent Closed-Loop Identification

NASA Astrophysics Data System (ADS)

Sobolic, Frantisek M.

Retrospective cost adaptive control (RCAC) is a discrete-time direct adaptive control algorithm for stabilization, command following, and disturbance rejection. RCAC is known to work on systems given minimal modeling information which is the leading numerator coefficient and any nonminimum-phase (NMP) zeros of the plant transfer function. This information is normally needed a priori and is key in the development of the filter, also known as the target model, within the retrospective performance variable. A novel approach to alleviate the need for prior modeling of both the leading coefficient of the plant transfer function as well as any NMP zeros is developed. The extension to the RCAC algorithm is the use of concurrent optimization of both the target model and the controller coefficients. Concurrent optimization of the target model and controller coefficients is a quadratic optimization problem in the target model and controller coefficients separately. However, this optimization problem is not convex as a joint function of both variables, and therefore nonconvex optimization methods are needed. Finally, insights within RCAC that include intercalated injection between the controller numerator and the denominator, unveil the workings of RCAC fitting a specific closed-loop transfer function to the target model. We exploit this interpretation by investigating several closed-loop identification architectures in order to extract this information for use in the target model.

Targeted delivery of non-viral vectors to cartilage in vivo using a chondrocyte-homing peptide identified by phage display.

PubMed

Pi, Yanbin; Zhang, Xin; Shi, Junjun; Zhu, Jinxian; Chen, Wenqing; Zhang, Chenguang; Gao, Weiwei; Zhou, Chunyan; Ao, Yingfang

2011-09-01

Gene therapy is a promising method for osteoarthritis and cartilage injury. However, specifically delivering target genes into chondrocytes is a great challenge because of their non-vascularity and the dense extracellular matrix of cartilage. In our study, we identified a chondrocyte-affinity peptide (CAP, DWRVIIPPRPSA) by phage display technology. Subsequent analysis suggests that the peptide can efficiently interact specifically with chondrocytes without any species specificity. Polyethylenimine (PEI) was covalently modified with CAP to construct a non-viral vector for cartilage-targeted therapy. To investigate the cartilage-targeting property of the CAP-modified vector, FITC-labeled CAP conjugated PEI/DNA particles were injected into rabbit knee joints, and visualized under confocal microscope. Higher concentrations of CAP-modified vector were detected in the cartilage and specifically taken up by chondrocytes compared with a randomly scrambled peptide (SP)-modified vector. To evaluate cartilage-targeting transfection efficiency, the GFP and luciferase genes were delivered into knee joints using CAP- and SP-modified PEI. Cartilage transfections mediated by CAP-modified PEI were much more efficient and specific than those by SP-modified PEI. This result suggests that CAP-modified PEI could be used as a specific cartilage-targeting vector for cartilage disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Planar optical waveguide based sandwich assay sensors and processes for the detection of biological targets including protein markers, pathogens and cellular debris

DOEpatents

Martinez, Jennifer S [Santa Fe, NM; Swanson, Basil I [Los Alamos, NM; Grace, Karen M [Los Alamos, NM; Grace, Wynne K [Los Alamos, NM; Shreve, Andrew P [Santa Fe, NM

2009-06-02

An assay element is described including recognition ligands bound to a film on a single mode planar optical waveguide, the film from the group of a membrane, a polymerized bilayer membrane, and a self-assembled monolayer containing polyethylene glycol or polypropylene glycol groups therein and an assay process for detecting the presence of a biological target is described including injecting a biological target-containing sample into a sensor cell including the assay element, with the recognition ligands adapted for binding to selected biological targets, maintaining the sample within the sensor cell for time sufficient for binding to occur between selected biological targets within the sample and the recognition ligands, injecting a solution including a reporter ligand into the sensor cell; and, interrogating the sample within the sensor cell with excitation light from the waveguide, the excitation light provided by an evanescent field of the single mode penetrating into the biological target-containing sample to a distance of less than about 200 nanometers from the waveguide thereby exciting the fluorescent-label in any bound reporter ligand within a distance of less than about 200 nanometers from the waveguide and resulting in a detectable signal.

Screening for basic drugs in equine urine using direct-injection differential-gradient LC-LC coupled to hybrid tandem MS/MS.

PubMed

Stanley, Shawn M R; Foo, Hsiao Ching

2006-05-19

A rapid, selective and robust direct-injection LC/hybrid tandem MS method has been developed for simultaneous screening of more than 250 basic drugs in the supernatant of enzyme hydrolysed equine urine. Analytes, trapped using a short HLB extraction column, are refocused and separated on a Sunfire C(18) analytical column using a controlled differential gradient generated by proportional dilution of the first column's eluent with water. Independent data acquisition (IDA) was configured to trigger a sensitive enhanced product ion (EPI) scan when a multiple reaction monitoring (MRM) survey scan signal exceeded the defined criteria. The decision on whether or not to report a sample as a positive result was based upon both the presence of a MRM response within the correct retention time range and a qualitative match between the EPI spectrum obtained and the corresponding reference standard. Ninety seven percent of the drugs targeted by this method met our detection criteria when spiked into urine at 100 ng/ml; 199 were found at 10 ng/ml, 83 at 1 ng/ml and 4 at 0.1 ng/ml.

3D map of theranostic nanoparticles distribution in mice brain and liver by means of X-ray Phase Contrast Tomography

NASA Astrophysics Data System (ADS)

Longo, E.; Bravin, A.; Brun, F.; Bukreeva, I.; Cedola, A.; Fratini, M.; Le Guevel, X.; Massimi, L.; Sancey, L.; Tillement, O.; Zeitoun, P.; de La Rochefoucauld, O.

2018-01-01

The word "theranostic" derives from the fusion of two terms: therapeutic and diagnostic. It is a promising research field that aims to develop innovative therapies with high target specificity by exploiting the therapeutic and diagnostic properties, in particular for metal-based nanoparticles (NPs) developed to erase cancer. In the framework of a combined research program on low dose X-ray imaging and theranostic nanoparticles (NPs), high resolution Phase-Contrast Tomography images of mice organs injected with gadolinium and gold-NPs were acquired at the European Synchrotron Radiation Facility (ESRF). Both compounds are good X-ray contrast agents due to their high attenuation coefficient with respect to biological tissues, especially immediately above K-edge energy. X-ray tomography is a powerful non-invasive technique to image the 3D vasculature network in order to detect abnormalities. Phase contrast methods provide more detailed anatomical information with higher discrimination among soft tissues. We present the images of mice liver and brain injected with gold and gadolinium NPs, respectively. We discuss different image processing methods used aiming at enhancing the accuracy on localizing nanoparticles.

Biomedical HIV Prevention Including Pre-exposure Prophylaxis and Opiate Agonist Therapy for Women Who Inject Drugs: State of Research and Future Directions.

PubMed

Page, Kimberly; Tsui, Judith; Maher, Lisa; Choopanya, Kachit; Vanichseni, Suphak; Mock, Philip A; Celum, Connie; Martin, Michael

2015-06-01

Women who inject drugs (WWID) are at higher risk of HIV compared with their male counterparts as a result of multiple factors, including biological, behavioral, and sociostructural factors, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this article, we discuss the need for expanded prevention interventions for WWID, focusing on 2 safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). Although both interventions are well researched, they have not been well examined in the context of gender. We discuss the drivers of women injectors' higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for WWID. There is substantial potential for impact of OAT and PrEP programs for WWID in the context of broader gender-responsive HIV prevention initiatives. Although awaiting efficacy data on other biomedical approaches in the HIV prevention research "pipeline," we propose that the scale-up and implementation of these proven, safe, and effective interventions are needed now.

Fuel Optimal, Finite Thrust Guidance Methods to Circumnavigate with Lighting Constraints

NASA Astrophysics Data System (ADS)

Prince, E. R.; Carr, R. W.; Cobb, R. G.

This paper details improvements made to the authors' most recent work to find fuel optimal, finite-thrust guidance to inject an inspector satellite into a prescribed natural motion circumnavigation (NMC) orbit about a resident space object (RSO) in geosynchronous orbit (GEO). Better initial guess methodologies are developed for the low-fidelity model nonlinear programming problem (NLP) solver to include using Clohessy- Wiltshire (CW) targeting, a modified particle swarm optimization (PSO), and MATLAB's genetic algorithm (GA). These initial guess solutions may then be fed into the NLP solver as an initial guess, where a different NLP solver, IPOPT, is used. Celestial lighting constraints are taken into account in addition to the sunlight constraint, ensuring that the resulting NMC also adheres to Moon and Earth lighting constraints. The guidance is initially calculated given a fixed final time, and then solutions are also calculated for fixed final times before and after the original fixed final time, allowing mission planners to choose the lowest-cost solution in the resulting range which satisfies all constraints. The developed algorithms provide computationally fast and highly reliable methods for determining fuel optimal guidance for NMC injections while also adhering to multiple lighting constraints.

Image counter-forensics based on feature injection

NASA Astrophysics Data System (ADS)

Iuliani, M.; Rossetto, S.; Bianchi, T.; De Rosa, Alessia; Piva, A.; Barni, M.

2014-02-01

Starting from the concept that many image forensic tools are based on the detection of some features revealing a particular aspect of the history of an image, in this work we model the counter-forensic attack as the injection of a specific fake feature pointing to the same history of an authentic reference image. We propose a general attack strategy that does not rely on a specific detector structure. Given a source image x and a target image y, the adversary processes x in the pixel domain producing an attacked image ~x, perceptually similar to x, whose feature f(~x) is as close as possible to f(y) computed on y. Our proposed counter-forensic attack consists in the constrained minimization of the feature distance Φ(z) =│ f(z) - f(y)│ through iterative methods based on gradient descent. To solve the intrinsic limit due to the numerical estimation of the gradient on large images, we propose the application of a feature decomposition process, that allows the problem to be reduced into many subproblems on the blocks the image is partitioned into. The proposed strategy has been tested by attacking three different features and its performance has been compared to state-of-the-art counter-forensic methods.

Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles.

PubMed

Sugo, Tsukasa; Terada, Michiko; Oikawa, Tatsuo; Miyata, Kenichi; Nishimura, Satoshi; Kenjo, Eriya; Ogasawara-Shimizu, Mari; Makita, Yukimasa; Imaichi, Sachiko; Murata, Shumpei; Otake, Kentaro; Kikuchi, Kuniko; Teratani, Mika; Masuda, Yasushi; Kamei, Takayuki; Takagahara, Shuichi; Ikeda, Shota; Ohtaki, Tetsuya; Matsumoto, Hirokazu

2016-09-10

Despite considerable efforts to develop efficient carriers, the major target organ of short-interfering RNAs (siRNAs) remains limited to the liver. Expanding the application outside the liver is required to increase the value of siRNAs. Here we report on a novel platform targeted to muscular organs by conjugation of siRNAs with anti-CD71 Fab' fragment. This conjugate showed durable gene-silencing in the heart and skeletal muscle for one month after intravenous administration in normal mice. In particular, 1μg siRNA conjugate showed significant gene-silencing in the gastrocnemius when injected intramuscularly. In a mouse model of peripheral artery disease, the treatment with myostatin-targeting siRNA conjugate by intramuscular injection resulted in significant silencing of myostatin and hypertrophy of the gastrocnemius, which was translated into the recovery of running performance. These data demonstrate the utility of antibody conjugation for siRNA delivery and the therapeutic potential for muscular diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy

PubMed Central

Sen, Malabika; Thomas, Sufi. M.; Kim, Seungwon; Yeh, Joanne I.; Ferris, Robert L.; Johnson, Jonas T.; Duvvuri, Umamaheswar; Lee, Jessica; Sahu, Nivedita; Joyce, Sonali; Freilino, Maria L.; Shi, Haibin; Li, Changyou; Ly, Danith; Rapireddy, Srinivas; Etter, Jonathan P.; Li, Pui-Kai; Wang, Lin; Chiosea, Simion; Seethala, Raja R.; Gooding, William. E.; Chen, Xiaomin; Kaminski, Naftali; Pandit, Kusum; Johnson, Daniel. E.; Grandis, Jennifer R.

2013-01-01

Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable”. We developed a decoy targeting STAT3 and performed a phase 0 trial. Expression levels of STAT3 target genes were decreased in the head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexa-ethyleneglycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. PMID:22719020