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A dual sensor for the simultaneous amperometric monitoring of glucose and insulin, wherein the glucose probe is based on the biocatalytic action of glucose oxidase, and the insulin probe is based on the electrocatalytic activity of metal oxide. Further provided is an oxidase enzyme composite electrode with an internal oxygen-rich binder. The present invention also optionally includes metallizing components within the carbon paste to eliminate signals from interfering compounds. The present invention includes embodiments for both in vitro and in vivo uses.
1. An apparatus for producing a signal related to the concentrations of glucose and insulin, said apparatus comprising:
a first conductive composite comprising a glucose oxidase and a metal posited within a first cylindrical tube;
a second conductive composite comprising a RuOx or IrOx catalyst posited within a second cylindrical tube;
a sleeve containing the first cylindrical tube and the second cylindrical tube;
a first electrical contact within the first cylindrical tube in contact with the first conductive composite; and
a second electrical contact within the second cylindrical tube in contact with the second conductive composite.
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9. An apparatus for producing a signal related to the concentration of a substance, said apparatus comprising:
a first conductive composite comprising an oxygen-dependent enzyme and sufficient oxygen-rich binder to support an oxygen-dependent enzymatic reaction in the absence of exogenous oxygen,
a second conductive composite comprising a RUOx or IrOx catalyst;
a sleeve with a first end and second end;
a first cavity disposed within the first end of said sleeve wherein the length of the sleeve is at least about 0.2 mm, said cavity containing said first composite and forming an electrode end of said composite at the first end of said sleeve;
a second cavity containing said second composite; and
an electrical contact disposed within the second end of said sleeve extending into said cavity;
wherein the ratio of the surface area of the electrode end of said composite to the volume of said composite is at least about 1:8.
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27. A method of simultaneous detection of glucose and insulin in a liquid sample, the method comprising the following steps:
a) providing a first screen-printed, thick-film biosensor comprising glucose oxidase;
b) providing a second screen-printed, thick-film biosensor comprising a metal oxide catalyst;
c) simultaneously placing the first biosensor and the second biosensor in the liquid sample;
d) applying a detection potential to the first biosensor and the second biosensor;
e) detecting a biocatalytic signal at the first biosensor; and
f) detecting an electrocatalytic signal at the second biosensor wherein providing a first screen-printed, thick-film biosensor comprising glucose and providing a second screen-printed, thick-film biosensor comprising a metal oxide catalyst comprises providing a dual sensor test strip with the first screen-printed, thick-film biosensor and second screen-printed, thick-film biosensor disposed thereon.
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32. A method of detecting substrate concentration of an environment using a composite biosensor, the method comprising the following steps:
a) providing a biosensor comprising (1) a first conductive composite comprising sufficient oxygen-rich binder to support an oxygen-dependent enzymatic reaction in the absence of exogenous oxygen, a conductor, an oxygen-dependent enzyme, a first reservoir containing the first composite, and an electrode end of the first composite, wherein the ratio of the surface area of the electrode end of said first composite to the volume of said first composite is at least about 1:8, and (2) a second reservoir containing a second conductive composite comprising a metal oxide selected from the group consisting of RuOx and IrOx,
b) placing the biosensor in the environment, and
c) detecting the substrate concentration.
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This application is a continuation-in-part application of U.S. patent application Ser. No. 09/216,353, now abandoned entitled Oxygen-Rich Oxidase Enzyme Electrodes, to Joseph Wang and Fang Lu, filed on Dec. 18, 1998, and the specification thereof is incorporated herein by reference. This application claims the benefit of the filing of U.S. Provisional Patent Application Ser. No. 60/267,811, entitled Needle-Type Dual Microsensor for the Simultaneous Monitoring of Glucose and Oxygen, filed on Feb. 8, 2001, and of U.S. Provisional Patent Application Ser. No. 60/068,916, entitled Oxygen-rich Oxidase Enzyme Electrodes, filed on Dec. 29, 1997, and the specifications thereof are incorporated herein by reference.
The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of Grant No. 1 R01 RR14173-0 awarded by the U.S. Department of Health and Human Services awarded by the National Institutes of Health for the National Center for Research Resources.
1. Field of the Invention (Technical Field)
The present invention relates to dual microsensors for the simultaneous amperometric monitoring of glucose and insulin, and to oxygen-rich composite enzyme electrodes and their use in a range of substrate concentrations and environments severely depleted in oxygen.
2. Background Art
Diabetes mellitus is a chronic metabolic disorder that results from a total or partial deficiency of insulin. In order to manage care, including providing enhanced diabetes control, there is a recognized need for glucose monitoring, including the simultaneous detection of glucose and other analytes, including most particularly insulin. Insulin sensing is of significant importance for clinical diagnosis, because it serves as a predictor of diabetes, insulinoma and trauma. By simultaneously measuring both glucose and insulin, an insulin/glucose ratio can readily be determined, thereby providing a single point assay for diagnosis of insulinoma and the management of diabetes.
It is known to utilize a ruthenium-oxide (RuOx)-type catalytic film sensor for insulin detection at physiological pH. Gorski, W., Aspinwall, C., Lakey, J. R. T., Kennedy, R. T., J. Electroanal. Chem. 1997, 425, 191. RuOx sensors have been used, for example, to monitor insulin secretion from pancreatic β cells. However, this device cannot be used to detect glucose or other substances.
Oxidase-catalyzed enzymatic reactions play a major role in the development of enzyme-based biosensors (Clark, Jr., L. C., Sachs, G. Ann NY Acad. Sci. 1962, 148,133; Schultz, J. Sci. Amer. 1991(8), 64). The large number of commercially available oxidases opens up the prospects for the detection of important substrates (such as glucose, lactate, or cholesterol) in relevant clinical, food or biotechnological matrices.
The following reaction:
Common routes for minimizing the strong oxygen dependence include the replacement of oxygen with a non-physiological electron acceptor (Cass, A. E., Davis, G., Francis, G., et al., Anal. Chem. 1984 56, 667), or the use of a proper membrane coverage that improves the surface availability of oxygen (relative to the substrate) (Gough, D., Lucisano, J., Tse, P. Anal. Chem. 1985, 57, 2353; Fischer, V., Hidde, A., Herman, S., von Woedtke, T., Rebrin, K., Abel, P. Biomed. Biochim. Acta 1989,48,965).
Others in the field have approached the problem of a limited oxygen environment in various ways: Clark (U.S. Pat. No. 4,721,677 (1988)) relies upon an oxygen chamber with a membrane to hold oxygen extracted from the tissues; Zawodzinski et al. (U.S. Pat. No. 5,227,042 (1993)) utilizes a back supply (bubbling) of oxygen through a porous electrode; and Rishpon et al. (U.S. Pat. No. 5,082,550 (1992)) casts a perfluorosulfonic acid isomer as a film directly on the conductor surface of the electrode to supply oxygen. These approaches sometimes result in a rather bulky apparatus and cumbersome operation, and are not compatible with miniaturization. In addition, they do not address the additional problem of electroactive interferences that can strongly affect sensor output.
Others in the field who address the interference problem (but ignore the oxygen limitation problem) frequently use a platinized carbon to create a paste for the enzyme (Bennetto et al., U.S. Pat. No. 4,970,145 (1990); Maley et al., U.S. Pat. No. 5,616,222 (1997)). These methods decrease interference somewhat, but still function at higher potentials.
Carbon paste electrodes (CPEs), consisting of a mixture of graphite powder and an organic pasting liquid (commonly mineral oil), represent an attractive approach for the preparation of reagentless biosensors (Wang, J., Un, M. S. Anal. Chem. 1988, 60, 1545; Gorton, L. Electroanalysis 1995, 7,23). The pasting liquid serves not only for filling the crevices between the graphite particles, but results in an electrode that is fundamentally different from those (e.g., Pt, Au) commonly used for amperometric transduction. Common pasting liquids include mineral oil, parrafin oil, silicone grease, and bromonaphthalene.
U.S. Pat. No. 5,922,183 (1999), to Rauh, discloses a thin film matrix for detecting substances, including glucose, utilizing an enzyme biosensor, such as a glucose oxidase, and a hydrous metal oxide as a catalyst or "cofactor" in enzyme reactions. However, this approach does not provide for simultaneous detection of glucose and insulin utilizing catalytic detection of insulin.
This invention provides for a combined needle-type probe, integrating an amperometric glucose biosensor with an electrocatalytic insulin microsensor. Thus in the same needle body an insulin-sensitive RuOx-modified carbon-paste microelectrode is integrated with a metalized, such as rhodinized, carbon amperometric glucose b-biosensor. Despite substantial analyte concentration differences, with mM concentrations of glucose and nM concentrations of insulin, and the use of different transduction principles, the microsensors of the invention respond independently and rapidly to the corresponding target analytes, with no apparent cross reactivity.
This invention further successfully addresses problems encountered in many in vivo and in vitro monitoring electrodes, including oxygen dependence of oxidase enzyme electrodes and redox interferences, through the use of carbon paste biosensors with oxygen-yielding (e.g. fluorochemical) pasting liquids supplied in a reservoir within the needle-type sensor. Due to the high oxygen solubility in perfluorocarbons, such pasting liquids provide an internal supply of oxygen, and efficient operation of first-generation oxidase electrodes under oxygen-deficient conditions. The result is a composite (binder serves as the oxygen reservoir) bioelectrode that provides real-time in vivo or ex vivo, accurate monitoring of specific chemical environments within the body.
The invention includes an apparatus for producing signals related to the concentrations of both glucose and insulin, the apparatus including a first conductive composite including glucose oxidase and a metal posited within a first cylindrical tube; a second conductive composite including a metal oxide catalyst posited within a second cylindrical tube; a sleeve containing the first cylindrical tube and the second cylindrical tube; a first electrical contact within the first cylindrical tube in contact with the first conductive composite; and a second electrical contact within the second cylindrical tube in contact with the second conductive composite. In this apparatus, the first conductive composite can include a carbon powder conductor. The metal used in the first conductive composite can include rhodium, iridium, or ruthenium. The sleeve can optionally include a conductor, and can further include an insulating layer posited on the exterior the sleeve with a conducting layer posited on the insulating layer. The metal oxide catalyst used in the second conductive composite can include RuOx or IrOx. In one embodiment, the first cylindrical tube and the second cylindrical tube have an interior diameter of less than 500 Mm. The first conductive composite can include an oxygen-rich binder, which oxygen-rich binder may be a perfluorochemical, myoglobin, or hemoglobin. The perfluorochemical can include polychlorotrifluoroethylene.
In another embodiment, the invention provides an apparatus for producing a signal related to the concentration of a substance, the apparatus including a conductive composite including an oxygen-dependent enzyme and sufficient oxygen-rich binder to support an oxygen-dependent enzymatic reaction in the absence of exogenous oxygen; a sleeve with a first end and second end; a cavity disposed within the first end of said sleeve wherein the length of the sleeve is at least about 0.2 mm, said cavity containing said composite and forming an electrode end of said composite at the first end of said sleeve; and an electrical contact disposed within the second end of said sleeve extending into said cavity; wherein the ratio of the surface area of the electrode end of the composite to the volume of the composite is at least about 1:8. In this apparatus, the conductive composite can include a metal powder conductor. In another embodiment, the conductive composite can include a carbon powder conductor, including but not limited to a metalized graphite. The metalized graphite can include rhodium, iridium, or ruthenium. In the apparatus, the sleeve can include an insulator, which insulator may include polytetrafluoroethylene. In the apparatus, the cavity can include a diameter of between approximately 0.2 mm and approximately 5.0 mm, including a diameter of about 2.0 mm. The oxygen-rich binder can include a perfluorochemical, myoglobin, or hemoglobin, and in one embodiment a d perfluorochemical including polychlorotrifluoroethylene. The oxygen-dependent enzyme can include an oxidase enzyme, such as glucose oxidase. The apparatus can further include a protective membrane covering at least a portion of the electrode end conductive composite. This membrane may include polyurethane, polycarbonate, polyethylene glycol, polyvinyl chloride or polyhydroethylmethacrylate, and may further optionally include an oxygen-rich film, such as a film including Pluronic F-88 or a perfluorosulfonate isomer. The sleeve of the apparatus may include a needle.
The invention further provides a method of simultaneous detection of glucose and insulin in a liquid sample, the method including the steps of providing a first biosensor including glucose oxidase; providing a second biosensor including a metal oxide catalyst; simultaneously placing the first biosensor and the second biosensor in the liquid sample; applying a detection potential to the first biosensor and the second biosensor; detecting a biocatalytic signal at the first biosensor; and detecting an electrocatalytic signal at the second biosensor. The detecting steps may include amperometric detection or stripping potentiometry. The metal oxide catalyst can include RuOx or IrOx. The first biosensor may, in certain embodiments, include an oxygen-rich binder. In one embodiment, the first biosensor and second biosensor are placed within a common sleeve or housing, including a needle.
The invention further provides a method of detecting substrate concentration of an environment using a composite biosensor, the method including the step of providing a biosensor comprising a conductive composite comprising sufficient oxygen-rich binder to support an oxygen-dependent enzymatic reaction in the absence of exogenous oxygen, a conductor, an oxygen-dependent enzyme, a reservoir containing the composite, and an electrode end of the composite, wherein the ratio of the surface area of the electrode end of said composite to the volume of said composite is at least about 1:8, placing the biosensor in the environment, and detecting the substrate concentration.
The invention also provides a method of detecting substrate concentration of an environment using a composite biosensor, the method comprising providing a biosensor comprising a conductive composite comprising an oxygen-rich binder, a conductor, an enzyme, and a reservoir to hold the composite, placing the biosensor in the environment, and detecting the substrate concentration.
A primary object of the present invention is to provide a dual sensor for simultaneous detection of both glucose and insulin utilizing a patient blood or other bodily fluid specimen.
Another object of the present invention is to provide a dual sensor wherein glucose is detected by means of biocatalytic action of glucose oxidase and insulin is detected by means of electrocatalytic activity of ruthenium oxide.
Another object of the present invention is to provide a dual sensor that provides accurate readings for triggering proper alarms and making valid therapeutic decisions.
Another object of the present invention is to utilize perfluorochemicals in a bioelectrode to provide an internal oxygen source.
Yet another object is to provide an interference-free bioelectrode for use in oxygen-deficient environments.
A primary advantage of the present invention is that it provides for simultaneous measurement of both glucose and insulin, utilizing different but compatible transduction principles.
Another advantage of the present invention is that it provides a miniature, needle-type dual sensor that may be employed as an implantable sensor.
Another advantage is the lack of need for an exogenous oxygen source or supply.
Another advantage of the present invention is the increased accuracy and selectivity due to lessened interference.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating a preferred embodiment of the invention and are not to be construed as limiting the invention. In the drawings:
A dual sensor is provided for the simultaneous amperometric monitoring of glucose and insulin, wherein the glucose probe is based on the biocatalytic action of glucose oxidase, and the insulin probe is based on the electrocatalytic activity of ruthenium oxide. In one embodiment, the dual sensor is miniturized, such that both electrodes, formatted as carbon-paste working electrodes, may be inserted into a 14-guage needle. Under flow injection conditions the dual sensors exhibit very rapid response to dynamic changes in the concentrations of both glucose and insulin. No apparent cross reactivity is observed in mixtures containing millimolar (mM) glucose and nanomolar (nM) insulin concentrations. The response is linear, to at least 1000 nM insulin and 14 mM glucose, and reproducible.
Glucose sensor 36 may conventionally be a glucose enzyme microelectrode. A metallized carbon-paste glucose microelectrode is prepared, such as by mixing 10 mg of glucose oxidase with 100 mg of rhodium-containing carbon paste, made from 40% rhodium-on-carbon, containing 5% rhodium, and 60% mineral oil, w/w. The paste is packed into the end of a 7 cm long Teflon® tube, with a 250 μm interior diameter and 600 μm outside diameter. The paste filled the tip to a height of 5 mm, with electrical contact to the inner end made with a 0.2 mm diameter copper wire.
Insulin sensor 40 may conventionally be an insulin-sensitive RuOx-modified electrode. A carbon paste is made by mixing 70% graphite powder, riot containing any metal, with 30% mineral oil, w/w, for approximately 20 minutes. A 7 cm long tube with a 250 μm interior diameter and 600 μm outside diameter is filled with the paste to a height of 5 mm, with electrical contact to the inner end made with a 0.2 mm diameter copper wire. The resulting carbon paste microelectrode is then electrochemically treated in 0.1 M KNO3 medium by polarizing at 1.8 V against Ag/AgCl (3 M KCl) for thirty seconds, followed by scanning the potential between −1.0 and 1.6 V at 100 mV/second for ten cycles, all in the same solution. The electrode was then rinsed, and the RuOx film electrochemically deposited. The RuOx film is electrochemically deposited on the carbon paste electrode surface from a 0.3 mM RuCl3 and 10 mM HClO4 solution, by cycling potential between −0.8 and 0.65 V at 10 V/second for twenty-five minutes. Electrode modification is initiated immediately upon dissolving the RuCl3 in the HClO4 solution. The electrochemical deposition was conducted using a three-electrode system, with an Ag/AgCl reference electrode and a platinum wire counter electrode.
The surface of a 14-gauge stainless steel needle was coated with an insulation ink to form thin film insulating layer 32, with an approximately thickness of 50 μm. Insulating layer 32 was cured at 110° C. for 30 minutes. Ag/AgCl layer 30 was coated on insulating layer 32 and cured for 30 minutes in an oven. Glucose sensor 36 and insulin sensor 40 are then inserted into the needle body.
In alternative embodiments, the selectivity and stability of electrocatalytic insulin microsensors can be increased. While metal-oxide catalysts, such as RuOx and IrOx are highly sensitive and permit rapid detection of nM insulin levels, there is the potential of interference from other oxidizable constituents of biological fluids. Due to the large size of the insulin target, common permselective coatings, such as those based on size or charge exclusion, cannot be used for preferential transport of insulin. However, hydrophobic lipid layers may be employed as a permselective coating, permitting transit of insulin but not other potentially interfering substances. Thus in one embodiment a mixed phospholipid and cholesterol film is employed, which is highly effective at rejecting small hydrophilic molecules, such as ascorbate, acetaminophen or urete, while allowing the transport and detection of large biomolecules, such as insulin. In addition, cholesterol doping of a phospholipid film imparts significant mechanical stability to such film. Thus the metal-oxide catalyst layer, such as electrochemically deposited RuOx, may be covered with a lipid film, including a phospholipid film containing cholesterol. Alternatively, RuOx, or another suitable metal-oxide catalyst, may be dispersed with a permselective layer, which layer includes a phospholipid film, optionally containing cholesterol. The film thickness and phospholipid/cholesterol ratio may be varied, thereby varying one or more parameters, such as insulin response time, dynamic range, insulin/interferant discrimination and operational stability/surface protection.
In an alternative embodiment, stripping protocols may be employed for measurement of insulin and glucose levels. This measurement protocol may be employed with dual sensor test strips. The majority of personal blood glucose meters utilize a disposable, generally screen-printed, enzyme electrode test strips, produced by thick-film microfabrication technology. A dual glucose and insulin test strip can couple common chronoamperometric measurements of glucose with highly sensitive stripping detection of insulin. Adsorptive stripping protocols may be employed with cartoon electrodes to measure insulin levels, including single-use thick-film carbon transducers. Different carbon inks, printing and activation conditions, as well as relevant variables of the stripping protocol, such as accumulation potential and time, stripping mode and environmental conditions, may be employed. Solution pH, ionic strength and the interfering effect of biomacromolecules can also be examined.
The invention further provides an oxygen-dependent enzyme carbon paste electrode (CPE) having an internal oxygen binder that can be utilized in low oxygen environments with little effect from interference. The invention addresses two problems encountered with electrodes used in oxygen-depleted environments. The first problem addressed is that of oxygen demand. It is well known that the solubility of oxygen in some organic solvents is many times greater than in water (Umland, J. General Chemistry, 1st Ed, West Publishing Co., St Paul, 1993, p. 962; Wilhelm, E., Battino, R. Chem Reviews, 1973, 73, 1). In particular, due to the very high oxygen solubility in fluorochemicals (resembling that of hemoglobin), such solvents have been used as oxygen transporters and blood substitutes in humans and animals (Clark, Jr., L. C., Gollan, F. Science 1966, 152, 1755; Ho, C., Ju, L. Baddour, R. Biotechnol. Bioeng. 1990, 38,1110; Millard, R. W. J. Artificial Cells Blood Substitutes Immobil. Biotech. 1994, 22,235). Taking advantage of this remarkable oxygen solubility, the invention uses novel oxygen-insensitive first-generation oxidase electrodes based on fluorochemical carbon pastes (or other biocomposites based on oxygen-rich binders).
A preferred embodiment of the present invention, the fluorocarbon binder polychlorotrifluorethylene (Kei-F) fulfills the role of satisfying oxygen demand internally, thus eliminating the signal dependence on oxygen level, and also allows for a convenient paste preparation (unlike perfluorononane, which is too dry and requires a large liquid to carbon ratio). Binders other than Kel-F may also be used. For example, mineral oil may be used in combination with a perfluorochemical (such as Nafion), although mineral or oil alone does not provide a sustainable source of oxygen, and results in a rapid glucose response loss within the first 20 minutes. The oil binder may also contain a different additive (such as myoglobin, a natural oxygen binder) with or without the presence of perfluorocarbons.
In one embodiment, the ratio of surface area of the electrode to volume of the carbon paste electrode is at least about 1:8. For cylindrical electrodes, this may be determined by simple formulas for the volume of the cylinder (using the standard formula V=πr2h, where r is the radius and h is the height), with area of the electrode surface similarly determined. Thus the ratio of the surface areas (as in mm2) to the total volume of the electrode (as in mm), such as a carbon paste electrode, is at least about 1:8. This provides a sufficient volume of internal oxygen binder to conduct measurements in an oxygen-depleted environment, wherein the sole source of oxygen for the oxygen-dependent enzymatic reaction is the internal oxygen binder. For example, assume a 2 mm diameter electrode, which would consume about 6×10−11 M/minute of oxygen in an enzymatic reaction, assuming that the applied current reflects about 10% of the resulting peroxide product. Based on an effective oxygen solubility in fluorocarbon oil of around 6 mM, the amount of stored oxygen for an 8 mm high cylindrical-shaped electrode would be about 1.2×10−7 M, thereby providing sufficient oxygen for over 40 hours of actual operation. Smaller ratios than 1:8 may also employed in the invention; for example, a 2 mm diameter electrode in a 2 mm high cylindrical-shaped electrode would still have about 4×10−8 M stored oxygen, sufficient for over about 40 hours of operation. However, the method of this invention must be distinguished from applications wherein a coating or thin layer is provided which, even if including a fluorocarbon, would contain only sufficient oxygen to support an oxygen-dependent enzymatic reaction, in the absence of endogenous oxygen, for a few seconds or at most, a few minutes. Oxygen consumption depends on the quantity of oxygen-dependent enzyme exposed to the analyte, and this in turn is directly related to the surface area of the electrode. With a small surface area a correspondingly small quantity of enzyme is exposed to analyte. Thus small surface area electrodes, with large reservoirs containing oxygen-rich binder, may be employed in environments which otherwise contain no oxygen.
Stabilization of the enzyme in a carbon paste environment is of major significance in view of the limited stability of enzyme electrodes at human physiologic temperatures (Frew, J., Hill, H. A. Anal. Chem. 1987, 59,933A-938A). The carbon paste electrodes enhance thermal stability and storage life, and allow for a prolonged high-temperature (e.g. 60° C.) stress.
A second problem addressed by the present invention in conjunction with the oxygen dependence problem is the interference to the signal provided by electroactive substances such as acetaminophen, ascorbic acid, salicylic acid, and some amino acids. The present invention uses electrocatalytic metal-dispersed materials to eliminate redox interferences. Metalized carbon bioelectrodes allow quantitation of a signal over the entire potential range, versus mediator-based sensor, which starts at 0.0 V. A preferred embodiment of the invention uses rhodium, or alternatively, ruthenium, dispersed within the carbon paste to allow signal detection at low potentials where interfering reactions are eliminated. These carbon paste compounds shift the detection potential for hydrogen peroxide to near zero volts. The enhanced catalytic action of these metal-laden pastes, compared to pure metal surfaces, is due to the three-dimensional distribution of metal sites within the plastic matrix. Microporosity leads to a preferential access of small particle species towards catalytic centers.
Because the enzyme is incorporated into the carbon paste, and as the need for anti-interference and diffusion limiting membrane is eliminated, at most only a protective biocompatible coating is needed for the bioelectrode, thus reducing the complexity of the apparatus. The coating can be purely protective, such as polyethylene oxide, polyurethane, polycarbonate, polyvinyl chloride, or polyhydroxyethylmethacrylate. Alternatively, it may also contain an oxygen-rich film, such as Pluronic F48 or Nafion.
The invention is further illustrated by the following non-limiting examples.
Cyclic voltammetry was conducted using a modular electrochemical system, with flow injection amperometric data collected using voltammetric analyzers with recorders. A standard flow injection system was utilized. Currents were measured in two electrode systems, with stainless steel and Ag/AgCl serving as reference electrodes for glucose and insulin measurements, respectively. Voltages are against the relevant reference electrode.
The concentration of RuOx and plating time in the electrochemical deposition were determined. Insulin response increased rapidly with the RuOx plating time up to a plating time of about ten minutes, and leveled off at a plating time of about above twenty minutes. The effect of detection potential was also determined. Insulin anodic response started at +0.3 V, rose sharply to about +0.55 V, and leveled off at higher values. Reported data was obtained utilizing a 25 minute RuOx plating time and a detection potential of +0.6 V.
Stability of the needle detector of
Experiments relating to an oxygen-rich binder were carried out with the BAS CV-27 volammetric analyzer (BAS, W. Lafayette), in connection with a BAS X-Y-t recorder. The enzyme electrode, reference electrode (Ag/AgCl, Model RE-1, BAS), and platinum wire auxiliary electrode joined the 10 mL cell (Model VC-2, BAS) through holes in its Teflon cover. A magnetic stirrer provided the convective transport during the amperometric measurement.
Enzyme electrodes were prepared by mixing 10 mg of glucose oxidase (GOx) with 100 mg carbon paste containing 75% Kel-F oil (poly(chlorotrifluoroethylene)) and 25% graphite powder (Rh-on-C, Aldrich, Milwaukee, Wis.). Mixing proceeded for an additional 30 minutes. A portion of the resulting paste was packed tightly into the cavity (3 mm diameter, 2 mm depth) of a BAS voltammetric electrode (Model MF-2010). The electrode surface was smoothed on a weighing paper. Carbon paste biosensors based on other pasting liquids or formulations were prepared in a similar fashion. The Kel-F/GOx-carbon paste microelectrode was prepared by packing the paste into the end of a on long Teflon tube (0.2 mm i.d., 0.6 mm o.d.). The paste filled the tip to a height of 8 mm, with electrical contact to its inner end made with a 0.1-mm diameter copper wire.
All solutions were prepared from double-distilled water. Glucose, glucose oxidase (EC 188.8.131.52, Type X-S, Aspergillus Niger, 135,000 U/g), o-phenylenediamine, sodium acetate and glucose (all reagent grade from Sigma (St. Louis, Mo.) were used without further purification. Kel-F oil (#10) was purchased from Ohio Valley Specialty Chemical (Marietta, Ohio). The rhodium-on-carbon (5% Rh), mineral oil, heptane and perfluorosulfonate (Nafion) (Aldrich, Milwaukee, Wis.) solution (5% by weight in a mixture of lower aliphatic alcohols and water, ER 1,100) were obtained from Aldrich. The paraffin oil (PX0047-1) and dodecane (DX24151) were purchased from EM Science. All measurements were performed in a 0.05 M phosphate buffer solution (pH 7.4).
Oxygen removal was accomplished by purging the solution with helium for 40 minutes; a helium atmosphere was subsequently maintained over the solution. There was thus no source of oxygen present other than as contained in the CPE. Experiments were performed by applying the desired potential (usually +0.06 V), stirring the solution at 300 rpm, allowing the transient background current to decay to a steady-state value (in the presence of the blank solution), and spiking the glucose substrate. All experiments were conducted at room temperature.
A preferred embodiment of the invention was used with glucose oxidase as the enzyme. Other oxidase enzymes may also be used in the invention, e.g. lactate oxidase aid cholesterol oxidase.
As expected for oxygen-deficit conditions, the polymer-entrapped enzyme electrode did not respond to the substrate additions (A,b), while the mineral-oil carbon paste biosensor displayed greatly reduced signals (B,b). In contrast, the inclusion of the perfluoropolymer Nafion in the mineral oil (C) or use of the Kel-F (poly(chlorotrifluoroethylene)) oil binder (D) dramatically minimized this oxygen dependence, and resulted in a similar response for nondeaerated and helium-saturated solutions. This thus demonstrates that the sole source of oxygen utilized by the oxygen-dependent enzyme was as included in perfluorpolymer Nafion, or in the Kel-F.
Despite the absence of oxygen, no reduction in the upper limit of linearity of the fluorocarbon-based electrodes was observed, with linearity prevailing up to about 1×10−2 M, and only a slight curvature thereafter. Apparently, these oxygen-rich fluorocarbon environments supply sufficient oxygen to satisfy the enzymatic reaction even under severe oxygen deprivation. Indeed, the Kel-F/GOx carbon paste electrode displayed a total oxygen independence up to a glucose concentration of 4×102 (not shown). Such oxygen independence is superior to that of most effective mediators (ferrocene) or wired (osmium) bioelectrodes, which display some oxygen competition for the enzyme. A nearly oxygen independence was obtained also using perfluorononane (CF3(CF2)7CF3) as pasting liquid, but the resulting paste was dry and required a large liquid/graphite ratio (10:1).
While the solubility of oxygen within fluorocarbons in approximately 25-fold higher than in water, oxygen solubilities in short-chain hydrocarbons are about 10 times higher than in water, and two-fold larger than in mineral oil (Wilhelm, E., Battino, R. Chem. Reviews 1973, 73,1; Lowe, K. D. Science Progress 1997, 80, 169; Sawyer, D. "Oxygen Chemistry", Oxford University Press, New York, 1991, p. 21). Hence, carbon-paste enzyme electrodes based on heptane or dodecane pasting liquids displayed a greatly reduced oxygen dependence in comparison to their mineral oil counterpart (not shown). However, their oxygen insensitivity was inferior to that of fluorocarbon-based biosensors. Perfluorochemicals are not saturable and can dissolve 50% of their volume with oxygen. Overall, the Kel-F CPE displayed the most favorable oxygen independence, sensing performance and surface consistency.
Lineweaver-Burke plots for the different fluorocarbon and hydrocarbon carbon paste biosensors were essentially linear (for glucose concentration in the range 5 to 60 mM, with and without oxygen; not shown). The resulting values of maximum current (Imax) and apparent Michalis-Menten constant (Km,app) are shown below in Table 1.
While similar Km,app and Imax values were observed for the fluorocarbon and hydrocarbon CPEs under_helium and air saturation, significantly different values were indicated for the ordinary (polymer and mineral oil) bioelectrodes. The higher values of Km,app (>35 mM) at the fluorocarbon and hydrocarbon bioelectrodes, in comparison with that (26 mM) of the soluble enzyme (Rogers, M. J., Brandt, KG. Biochemistry 1971, 10,4624; Swoboda, B., Massey, V. J. Biol. Chem. 1965, 240, 2209), indicated that their response is controlled partly by mass transport.
A key issue for addressing the oxygen demand of oxidase biosensors is the ability of the internal oxygen reservoir to reliably deliver oxygen over an extended period of time.
The confinement of GOx within fluorinated CPEs had no detrimental effect upon the enzyme activity. A nearly identical glucose response was obtained using the same Kel-F CPE surface (3 mm diameter) over a 75 day period, with intermittent storage at 4° C. Such Kel-F confinement resulted also in a remarkable thermal stability, as was indicated from the identical glucose response before and after a 24 hour stress at 90° C.
As illustrated in
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Although the invention has been described in detail with particular reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above are hereby incorporated by reference.
Patent Citations
Non-Patent Citations
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text:
When our first issue hit newsstands in 1992, the Dow was under 3500 and a "smartphone" had a cord running from the kitchen to the den. Here, eight lessons we learned along the way.
A brief accounting of what SmartMoney Magazine got right -- and wrong.
Can workers fight the weak economy by becoming full-time investors?
Moving to a residential-care facility is difficult enough -- even before you account for the hidden fees, untrained caretakers and misleading marketing.
As we hurry off into the history books, we can't help but make a few bold predictions about the future of finance.
Arends: The average hedge fund trounced the S&P 500 during the 2008 crash -- but has lagged it ever since.
Annuity providers are quietly tweaking the payouts on some of their popular products. Why the changes have advisers and investors up in arms.
Uncertainty over the fate of Europe and China has sent investors fleeing from emerging-market funds. So why are some pros heading back in?
Can't find the sale racks at Saks? That's exactly how the CEO likes it.
Investment pros have made a habit of -- and made money -- betting on the second-biggest company in an industry.
Budget cuts, increased regulations and changing technology are testing many education-related firms.
High crop prices could be a boon to farmers and investors alike. Two ways to buy into the world's growing demand for food.
Hough: Erratic price swings can work to the advantage of long-term investors.
Why have dozens of stock mutual funds made exchange-traded funds some of their largest positions?
Online consulting sites are enticing boomers with offers of freelance gigs. But can the jobs pay professionals the wages they want?
With some private colleges bumping up their financial aid, good old State U. is no longer always the cheapest option.
Ruffenach: When family battles over an elder are ready to boil over, it may be time to call in an expert.
Machan: Serving free ice cream and being nice to jerks: How small retailers survive.
With the markets once again turning shaky, we turned to the pros for advice.
As the lodging industry rebounds, big-name brands are checking in. Why everyone from top designers to sushi chef Nobu wants to be a hotelier.
Kadet: Our fascination with self-monitoring has created the lab-test junkie.
From private lessons to a music vacation, what you get for your money.
Which investments are undervalued and poised to grow? How can you make your portfolio cost-effective? Brett Arends, an inveterate bargain hunter, puts his skills to work answering these questions and more.
Which stocks will shine? Jack Hough searches the markets for clues that point to tomorrow's top performers.
From credit cards and charitable giving to online dating and the hunt for discontinued products, Anne Kadet takes an offbeat look at consumer behavior, customer service and marketing trends.
Small businesses are the engine of the economy; Dyan Machan finds out what kind of fuel makes them go. Innovation, strategy and tips for start-up entrepreneurs, in Smart Ideas.
For a growing number of baby boomers, there is no more pressing financial issue than retirement. Glenn Ruffenach looks at strategies, ideas and tools to help prepare for, and make the most of, life after 50.
If you think personal finance is all about math skills and timing, your brain has a surprise for you. Wall Street Journal editor Ryan Sager explores the intersection of psychology and investing in Money & Your Mind.

subset: commoncrawl


text:
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Novel by Clockworkk
Posted: Feb 19, 2013
Science can explain almost anything, but in some...
I'm basically a fifteen-year-old girl who wants to be an author (like many, I guess). Any critique/comments are always very much appreciated, don't be afraid to be honest because I honestly prefer it! I can't get better if I don't know.
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Kayla McCulley '09 Awarded NCAA Internship
Kayla McCulley '09, who played lacrosse at Pomona, has been awarded one of 19 postgraduate internships at the National Collegiate Athletic Association national office in Indianapolis. The program offers on-the-job learning and mentoring opportunities to graduates from NCAA institutions, who are interested in pursuing careers in intercollegiate athletics administration.
Since June 7, McCulley has been a member of the NCAA governance staff, which works directly with the presidential bodies and management councils that direct the affairs of the three NCAA divisions.
The position will give her a great deal of contact with the member schools and conference commissioners, she reports. "Over the course of the year, I will be involved with committees and legislation related to many sports and all three divisions."
An international relations major at Pomona, McCulley says her experience on the Pomona-Pitzer women's lacrosse team was formative in developing her interest in sports administration.
"I was a four-year member and senior captain for the lacrosse team [and] played defensive midfielder. During my sophomore year, the 2006-2007 season, women's lacrosse made the jump from a club sport to become an NCAA varsity program. That was definitely exciting for us as players and a great step forward for the Pomona-Pitzer athletic department. My lacrosse teammates became my closest friends at Pomona, and I couldn't imagine my experience there without sports."
After graduation, McCulley received a Fulbright research grant and traveled to Neuchatel, Switzerland to study policies and regulations governing the transfer system for professional soccer players in Europe. She also took sports law and sports geography classes at the International Centre for Sports Studies (CIES). Next month, she will travel to Ghent, Belgium, to present her research at the Association for the Study of Sport and the European Union Conference.


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Super User
Joined: 09 Feb 2003
Posts: 606
Location: Australia, mate!
Posted: Tue Nov 18, 2003 11:37 pm
Post subject:
There's a OOo to MSOffice converter here:
for those who neither want to wait for OOview, nor download OOo.
There, that should satisfy everyone.
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Posted: Wed Dec 03, 2003 2:57 pm
Post subject: Open Office Viewer
I refuse to install open office. The idea that i have to give 90 mbs of disk space to OOo and have it hog up my memory infuriates me
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General User
Joined: 21 Dec 2003
Posts: 29
Location: New York City
Posted: Sat Dec 27, 2003 9:15 pm
Post subject:
Sam I am wrote:
What about Impress? I'm converting all my slides from .ppt to .sxi. But I have to convert them back to .ppt as other machines (classroom computers at our university) don't have OOo installed.
If there is a viewer for .sxi, I can ditck MS forever.
Somewhere in this thread it's probably mentioned already, but in your case, using Impress, save the files as Flash and you are all set! They can watch the presentations in any web browser with Flash player installed. (OOo version 1.1 can export as Flash.)
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General User
Joined: 16 Nov 2003
Posts: 21
Posted: Thu Jan 08, 2004 3:02 pm
Post subject:
Jim Shackelford wrote:
A belated suggestion regarding a file viewer for Impress slideshows.
A good many of the presentations I've been involved with involve multiple presenters. The presenters have to either stop the presentation to hook up their own laptops or have a common laptop for use which can show each presentation. Since I can't install Open Office on someone else's laptop, I cannot use Impress. I either have to bite the bullet and do a Powerpoint or, as I prefer to do, use Corel Presentation to create a slideshow and then save it to an executable file. It is essentially a file viewer that incorporates the slidehow in it. No installation, no muss, no fuss. I think something similar would be very helpful for Impress users. The promise of a java viewer comes close but fails because it requires the runtime to be on someone else's laptop.
I had the same problem, and the solution is quite easy: You don't have to install OOo on the PC. Just burn your OOo installation (the already _installed_ files !) together with the presentation on a CDR. Start soffice.exe from CD, it takes some time to load as it's running from CD. When Office has started, just open the presentation.
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OOo Advocate
Joined: 11 May 2003
Posts: 279
Posted: Tue Jan 13, 2004 2:24 am
Post subject:
Happy New Year 2004 everyone.
I decided to search for an OOo viewer because my friend is japanese. She wrote a document using Japanese OOo instead of Word using Windows XP (Japanese too). However the document she wrote is in french (I'm french too... yes posting on an english community :p). Anyway she tried to save as Word but it seems OOo.jp can't handle french documents. I will probably post about it someday, just trying to fix it right now. Not the first time I report an OOo bug anyway
So I searched for « viewer » on the forum and found tons of topics. That one is the first, I also have to read 10 others... So here comes some thoughts, remarks and suggestions I had while reading the whole discussion (very interesting) :
- what is a SWX file ? (no association) : I mean no one knows what a SWX file, I'm not even sure that what SWX means. So when someone receives a SWX file, what should it do ? With a « readme.openoffice.writer » it could do something but SWX doesn't mean anything. Search for help on Google ? Visit the « SWX Swiss Exchange », « downloads.sybase.com/swd/swx », « MitekFactoryOutlet.com », etc... Nothing about OOo.
- what if you can't convert your document to Word ? (see my previous comment). That's why we could all use a SWX viewer. I should say an OpenOffice.org Writer Document viewer because SWX doesn't mean anything (3 letters extension...)
- Could use a IE, Nescape/Mozilla/Firebird OOo viewer (like PDF, Word...) : document viewer embedded in all your favorite applications (web browser, email client...)
- disk space, memory, install : so you would ask a user to wait for 2 hours to view a
single file ? It takes 2 mins to view a PDF document if Acrobat Reader is not installed, yet. Download (2 steps, see below) Acrobat Reader (only 16 MB), takes 2 mins to install, and voilà. You can view your PDF file. What about an OOo document ? Just try to download it (takes hours even for a computer guru like me), once you found a way to download it (see below),... Wait 30 mins (on my ADSL 512 connection) to download... Wait wait... Then I think you need to install JRE (!)... Wait... Install... If it works OOo is installed and you can view AND edit your file, it's not a viewer, it's an editor with tons of useless features to view the file. Who needs a Bold button of Format menu to view a file ?
- export to HTML/PDF : can't trust OOo when it comes to export, It can't handle my files (complex documents). Moreover converting a document from one format to an other means you will probably lose some information, I don't know of any converter that is 100% perfect.
- is there a SWX file reader/opener for MS Word ? Not sure... it would allow MS Office users to view SWX file. We think the OOo way but what about being more « open » to commercial applications ? I used to write my documents with MS Office and only switched to OOo because MS Office 97/2000 were too unstable and expensive. I don't think OOo should be the only « office suite », open is the way, alone is not a solution.
- Players we know (so players ARE useful) : Macromedia Flash Player, Adobe Acrobat Reader, MS Word Viewer, Winamp/Zoom Player (using OOo to view a file would be like using Adobe Premiere or Final Cut Pro to view a video)... Long is a the list
. I can't believe some people don't understand why an OOo player/viewer is ESSENTIAL. OOo is an office suite, to WRITE document first, not to VIEW them. Like Adobe Photoshop is an image editing tool... But IrfanView or ACDSee are viewers... To view « proprietary » Adobe PS files (.PSD). Just thinking that we could use a « document viewer » that supports PDF, DOC, RTF, HTML... That would be great
. I think IE really acts as a « beacon » to view documents (ActiveX rulez). UNO for OOo ?
- Send Document as : current features are not well implemented as you can't send your document as HTML, only SWX of PDF
. And that's the « open » way ? ^^.
- Steps to download OOo (from OpenOffice.org) : Download > « Latest Build: OpenOffice.org 1.1 » > « Latest Build: OpenOffice.org 1.1 » (again !) > « Installation Instructions & Guides, Windows & Linux » > Select Language... System... ?????????????????!!!!!!!!!!!!!!! NO ONE WILL EVER DOWNLOAD NOR TRY TO INSTALL A PRODUCT IN 10 STEPS. It's completely un-user-friendly.
- Steps to download Adobe Acrobat Reader (from
if you search for « acrobat reader » on Google you directly jump to the download page) : Select « Acrobat Reader » from the « Acrobat family » combobox or click the « Get Adobe Reader » button, Step 1 of 2 (2 steps !) : Language, Platform, Connection speed ; Step 2 of 2 (doesn't even reload the page) : click Download. AND VOILÀ.
These 2 last remarks really scared me. Seriously. I forgot how complex it was to download and install OOo. I mean no one « normal » would even try to install it. There's no « get » or « download » icon to quickly download and install OOo. See the Acrobat Reader way, 2 STEPS ! The website is anti user-friendly, hard to browse, hard to find info... And I gave up at 10 steps ! Then you have to wait, install, reinstall, try, launch... Longer, harder and weaker. The current, actual, boring OOo way. Faster, easier, stronger should be the way to go, the Acrobat Reader way. I can't believe they didn't market research these ways of architecturing their information on OOo.org. We have a lot to learn from Adobe and Microsoft. I think they forgot that, they chose the geek-way instead of the user-way. Why do complicated when you can do simple ? (french axiom, not sure of the translation).
Damn, that time I have been very hard on OOo but it's for the best. I also reported tons of bugs I found while writing my documents. And that's how things are and work, you have to tease the bug to make it better... Something like that. You can't just think that everyone is an OOo guru yet, nobody knows OOo. I mean NOBODY. It's new, SUN can't be compared to Microsoft when it comes to promote a product, an « office suite ». And EVERYBODY knows MS Office. So my idea is to think simple, think « user ». What does a user want to do with a document it receives ? It wants to view it. Not to edit it. Same goes for graphics files (JPG, PNG, GIF, photos), text documents (HTML, DOC, PDF...) or media files (videos, mp3s, songs, musics, trailers...). Viewers are USER FRIENDLY softwarers, editors are not meant for users but for editors, creators, professionals. If a user has installed Adobe Acrobat (Distiller), it can edit its PDF documents simply by clicking an edit button from the Acrobat Reader (Viewer), then the user becomes an editor, a creator. From user to editor.
I hope there's some OOo developers or architects around because I think our remarks could really help them (modestly ^^) to improve OOo. At least redesign the website because I can't even think about asking my girlfriend to jump into that mess. Maybe I should, just to see if I'm right. No no I'm sure, I know users (hope ^^). I also think the OOo Reader + Suite is not bad as It would allow « us » to convert a visitor to a reader, from the reader they could choose to download and install (One-Click ! -> Amazon :p) OpenOffice.org Suite. That's how things should be
All your remarks, comments and suggestions are welcome !
An OOo mascot designer
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General User
Joined: 16 Nov 2003
Posts: 21
Posted: Tue Jan 13, 2004 12:52 pm
Post subject:
Some very good points ! Especially the website could be a lot better. As a personal workaround, I mail friends the direct link.
Some corrections: It's a sxw-file, not swx. Doesn't help much on google though.
You don't have to install Java to install OOo. Just select "without java" during installation. OOo will give you a message that some features will not work, but it installs fine.
I can't follow your point why installing OOo is so hard. I think it's a piece of cake. Start setup.exe and follow instructions, you can't do much wrong.
I often give OOo CDs to friends. I have built a simple installer. It starts automatically when the CD is inserted, and offers a button "Install OpenOffice". Can't be easier than that. If there's enough interest, I can upload it, it's a simple script for wxbasic.
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Posted: Wed Jan 21, 2004 2:50 am
Post subject:
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OOo Advocate
Joined: 11 May 2003
Posts: 279
Posted: Wed Jan 21, 2004 5:33 am
Post subject:
o3read (
) is just a converter, not a stand alone viewer.[/url]
An OOo mascot designer
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Super User
Joined: 29 Nov 2003
Posts: 2130
Location: UK
Posted: Mon Feb 23, 2004 10:12 am
Post subject:
avantman42 has posted something relevant to this thread
click below:
OOo Viewer available (requires Java)
OOo site
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Posted: Thu Mar 04, 2004 6:18 am
Post subject:
I'd love to see a sxw - rtf converter dll just like MS Office has its MsWrd832.cnv and MSConv97.dll. Total Commander (www.ghisler.com) can use these dlls to view Word documents.
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Super User
Joined: 29 Nov 2003
Posts: 2130
Location: UK
Posted: Thu Mar 04, 2004 6:34 am
Post subject:
anvilsoup wrote:
There's a OOo to MSOffice converter here:
From the top of this page, rtf is one of the output formats available.
OOo site
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OOo Advocate
Joined: 11 May 2003
Posts: 279
Posted: Wed Apr 21, 2004 6:19 am
Post subject:
petameta wrote:
Some very good points ! Especially the website could be a lot better. As a personal workaround, I mail friends the direct link.
Has anyone noticed the beautiful new and well polished
link from the home page ?
3 steps :
- Click
- Select your language, OS...
- Download OOo from the nearest mirror
Next step would be to get 2 steps as the mirror can be automatically selected using the visitor IP.
An OOo mascot designer
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Posted: Sun May 02, 2004 7:24 pm
Post subject: viewer
A viewer would also good for distributing sxi presentation files.
Seems to be a very microsoft - like approach to assume that everyone has your software.
Since the export of ppt files from OO doesn't actually work (the MS viewer can't read them), the lack of a stand alone sxi viewer makes the OO impress app almost entirely useless for distributing presentations.
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General User
Joined: 30 Apr 2004
Posts: 25
Location: Omaha, NE
Posted: Sun May 02, 2004 8:12 pm
Post subject:
Seems to be a very microsoft - like approach to assume that everyone has your software.
Microsoft doesnt assume everyone has their software... you can export an executable package that contains your Powerpoint presentation and a special viewer application.
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Posted: Mon May 03, 2004 7:22 am
Post subject:
IndeView - Independent Presentation Viewer
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text:
Great program & many thanks.
First question as I try out program:
What determines the file order when Tag Editor is opened
and how can I change the order?
The order is supposed to be by track number (and the files are supposed to be from the same album). Files whose track numbers are missing are put at the end of the list and they are sorted by the file name. Since you're asking this, I guess your files either don't have track numbers or come from Vinyl or tape, where numbering might be different.
One way to change the order is to first assign track numbers manually and then press on the button with an arrow pointing down, called "Sort by track number".
However, I suspect that this isn't what you want, so I guess it would be better to post a list with your files from some folder / album and tell what you want to achieve (i.e. how would you want them sorted and why.)
(Ordering by track number is important when downloading or pasting album info.)


text:
Pinterest, LinkedIn and More !
On Tuesday, June 11 I, along with my co-worker Amy, attended the "Social Marketing Summit" presented by enterprise Toronto in partnership with Constant Contact. It was held at the North York Civic Centre in the Council Chamber which I must say was a great venue for the jam packed audience in attendance.
Being a public speaker myself, I do have a soft spot for other presenters trying to cover everything on their agenda within a short period of time and to an audience that spans a wide range of industries and varied levels of knowledge. Each session was held to a maximum of 45 minutes, so everyone needed to get their points across very succinctly.
Overall, I thought the day was well organized, with some of my own personal highlights being Lowell Brown's presentation on Pinterest, Ross Macpherson's session on LinkedIn and Marie Wiese's concluding seminar on the importance of your website as it pertains to your overall online presence.
I must admit that I was looking forward to this session because, quite frankly, Pinterest was an area of social media where I felt I had the most to learn. And although the presentation was probably basic for some, it was ideal for me, and I found it to be an engaging and educational experience. Here are some of the takeaways from Mr. Brown's general overview that I felt were important (in no particular order):
- Currently 48.7 million users (more than I thought)
- Most popular age group 25-34 with the majority of users being female
- Pinterest drives more referral traffic than Google+, LinkedIn and YouTube combined (WOW!)
- Pinterest has grown faster than any other independent site in history
- Pins containing prices get 36% MORE likes than those without
And here were some tips to make Pinterest most effective for your business. Some were basic –marketing 101 – but there still some great insights:
- Set goals for what you want to achieve with Pinterest for your business
- Know your target audience – what would be of interest to them?
- Use keywords everywhere – in account name if possible, about section, account profile, in each board description, pin description, etc.
- Create sharable content – great quality images, Use CTA's (Call To Action) on images and include URL on image
- Share your Pins on other social platforms and always link them back to your Pinterest account
The LinkedIn presentation was also well done, but for different reasons. My LinkedIn profile, which I had previously thought was quite good, needed more editing than I thought – and Ross certainly knew his stuff when it came to optimization for this particular part of social media.
Some of the more interesting facts he shared were:
- 87% trust LinkedIn as a source of information
- Most people spend less than 10 seconds on a profile
- Use a good photo of yourself – particularly if you are the face of your business
- Customize your headline – this is your branding statement (120 characters); pack it with value and SEO keywords; show who you work with, who you help, what problems you solve, etc.
- Make everything readable – illustrate your personality
- Make it creative and complete – make it your own, complete all applicable and relevant areas; include your contact info in your summary; make it easy to find
One of the great points to me was remember to TURN OFF broadcasts in your SETTINGS before you start so that all your connections don't get notified about every change you make. Equally important remember to turn it back on when you are done. J
- Make your summary (2000 characters) both personal and conversational but still professional
- Use short "chunks" of information (avoid long paragraphs)
- use keywords but don't overuse them
- Don't write the employment section like a resume – again make it personal
- GROUPS – join those that are relevant to your skills, services and industry; participate and get noticed
- Complete every section that is RELEVANT TODAY – nobody cares about your hobbies
- Use your profile to market yourself – showcase your value, resonate with your audience
The last session talked about the importance of your website, its role as your most important sales tool, and what to do to get a measurable ROI. I thought Marie's presentation on this topic was both articulate and smart (I'm sure my feelings about the presentation had nothing to do with the fact that I agreed with almost everything she said.
And again, the key takeaways for me:
- 97% of people searching for a solution start their search online
- Most buyers are 70% through the buying process before you ever hear from them
- Your web presence is NOT just about your website…it is everything you are doing online for your brand
- The message on your website should center on why what you do matters to your customer – not just what you do.
The Three Key Things You Need for Your Website to Work
- Have a message – clear, concise and different – what is your value proposition?
- Ensure you have a complete web presence – utilize all the online channels available to drive traffic to your website
- Measure the results (Use Analytics – test, measure, evaluate and test again – this one is a biggie, folks!)
She also included a brief but accurate list of Do's and Don'ts.
- Ask someone to marry you on the first date
- Try it once and say it doesn't work
- Try a tactic that doesn't have a clear objective
- Ignore your customer's buying process
- Be persistent – it takes five to seven communication touches to determine an action
- Always remember that Google Analytics is your friend – you cannot measure what you cannot track. You cannot track objectives you don't have.
So overall, a day well spent. Kudos to Enterprise Toronto and Constant Contact for making this event happen. And special kudos to each and every presenter for a job well done.
As always, your comments are welcome. Do you agree with these observations?
Talk to you soon.


text:
WikiLeaks is still in the secret-spilling business. But not, apparently, in the business of accepting those secrets through the anonymous dropbox that was once its trademark.
The site on Thursday unveiled a new trove of 287 documents it's calling the Spy Files, a collection of 160 digital surveillance firms' marketing materials, price lists and catalogues, a joint effort with Bugged Planet, The Bureau of Investigative Journalism, and Privacy International, and with a new cadre of media partners including the Washington Post, the Hindu, the Italian paper L'Espresso and the French news outlet OWNI. The documents, sorted by company name and dozens of types of surveillance such as spyware, Wifi interception, and cellphone forensics are broken down on a new section of WikiLeaks' site.
"Mass interception of entire populations is not only a reality, it is a secret new industry spanning 25 countries," a statement on the site reads. "International surveillance companies are based in the more technologically sophisticated countries, and they sell their technology on to every country of the world. This industry is, in practice, unregulated. Intelligence agencies, military forces and police authorities are able to silently, and on mass, and secretly intercept calls and take over computers without the help or knowledge of the telecommunication providers. Users' physical location can be tracked if they are carrying a mobile phone, even if it is only on stand by."
Included among the leaked documents are those from major companies like Alcatel-Lucent, Nokia-Siemens, HP, and dozens of smaller firms. But just how much previously unknown surveillance is revealed in the documents isn't clear, given that the last month already saw several major exposés of gear from Western tech firms sold to repressive regimes for censorship and spying. The Wall Street Journal last month dumped a similar cache of surveillance firm materials, releases from the hacker group Telecomix and the Canadian research group Citizen Lab have revealed Blue Coat's technology in Syria and Burma, while Bloomberg reports showed that NetApp, HP, Qosmos and Ultimaco all sold gear that was found in Syria's surveillance complex.
WikiLeaks has hinted that more documents will be released over time, and other revelations may surface as the public combs through the Spy Files. The French media outlet OWNI, for instance, has revealed a page of a manual from the French surveillance firm Amesys that includes a screenshot showing more than 40 pseudonyms of tracked figures. Many of those pseudonyms, OWNI has found, corresponded with political dissidents and activists that Libyan dictator Muammar Qaddafi had sought to jail or kill.
Meanwhile, one other long-awaited release from WikiLeaks has yet to come: Its new submission system. WikiLeaks founder Julian Assange had said in a press conference in October that the site would launch its new anonymous dropbox on November 28th, a year after its announcement of its Cablegate leak of 251,000 State Department documents. In a statement to press over the weekend titled "Online security and the reopening of the submission system," WikiLeaks had delayed that launch until Thursday, but still hinted at a "new phase" for the group.
In the announcement Thursday, no mention was made of that new dropbox. Kristinn Hrafnsson, WikiLeaks' Icelandic spokesperson, confirmed to me by phone that the new submissions platform is still not online.
Assange has blamed the delay of his new leak platform in part on vulnerabilities in the SSL encryption commonly used on websites, after a year that saw several of the companies ensuring the authenticity of encrypted sites compromised and used to issue fraudulent certificates. "Online security has become severely and irreversibly compromised over the past months," reads WikiLeaks' latest statement on the submissions platform from last week. "Over a year or longer, SSL certificates have been penetrated by various organised crime groups and intelligence agencies. The entire SSL system, which is the mechanism that guarantees security and anonymity online, has been compromised. SSL is beyond repair."
With its leak channel down for more than a year, just where the Spy Files came from isn't clear. One of WikiLeaks' partners, such as the surveillance-tech-focused Bugged Planet project run by Chaos Computer Club president and WikiLeaks associate Andy Muller-Maguhn, may have obtained the documents. Assange has also hinted that sources have still been able to send him anonymous documents through other channels.
"For the last 12 months, you haven't been able to go through the front door," to submit information to WikiLeaks, he said at October's press conference. "You've had to establish contacts with the organisation and transmit us the material through other mechanisms."
WikiLeaks' official submission system has been offline since former WikiLeaker Daniel Domscheit-Berg and at least one other engineer left the group in the fall of 2010, taking with them much of the control of its infrastructure and thousands of leaked documents, which they later deleted out of security concerns. Assange has since argued that the rise of online surveillance and the insecurity of Web infrastructure like SSL has made anonymity online harder than ever in WikiLeaks' history.
With this latest portrait of pervasive spying on the Internet, don't expect WikiLeaks' new strain of pessimism to brighten any time soon.


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- www.songuyen.com - review this website
- www.adrienpatout.com - review this website
Artist Songuyen abstract contemporary art modern paintings
Vietnam born artist living in Provence, South of France near Avignon. Self-learnt about abstract contemporary modern art and just follow his daily inspiration, what he see with his own eyes⦠He like to paint little small things.
This page was last updated on 05 Aug 2015 GMT v10.0
Adrien Patout - Illustrations, paintings and eye candies
Ilustrations, paintings and eye candies by Adrien Patout


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Hey guys, Daisy's OK.
You may have read TMZ's story regarding the "possible overdose" of Daisy of Love star Daisy De La Hoya. The official word is that it wasn't an overdose, but exhaustion that Daisy suffered. Here's VH1's statement on the matter:
"Daisy was taken to an ER early Thursday morning suffering from exhaustion. There was no overdose. She is fine this evening and resting comfortably. No further details are being released at this time."
Related content
Daisy of Love show pages
Daisy of Love full episodes, show clips and bonus scenes
Daisy De La Hoya – Exclusive Video Interview


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Presenting you a wireless mouse that is modern, touch-sensitive and easily portable; which is most important if you want to enjoy in the mobility that your portable computer can provide. Microsoft has made a mouse that can give you the easiest portability, combined with the most elegant design and the option to use your mouse on many different surfaces.
Microsoft's arc touch mouse is unique in its style, performance and feel, featuring an innovative design that curves to fit comfortably in the palm of your hand yet packs away flat for easy storage, portability and transport. This flexible design is perfect for your mobile life style.
Microsoft's arc touch mouse is touch sensitive and gives you speed and responsiveness at the touch of your fingers. This mouse is quite versatile with five buttons in total. Microsoft's arc touch mousehas a Nano-Tranceiver which is compatible with windows and you can connect wirelessly without any setting up. The micro usb receiver is tiny and plugs in so you never need to remove it again.
Microsoft's blue track technology can track on variety on different surfaces including rough wood, glossy granite or soft carpet; however the blue track technology won't work on clear glass or mirrored surfaces.
Microsoft's arc touch mousehas a power saving feature that saves battery. Simply curve the it to turn it on and flatten it to turn it off. The battery life can last up to six months and the mouse comes with two triple A batteries.
Microsoft has even made a web portal where you can enjoy creating some great pictures using your own arc touch mouse and it is supposed to be one of the biggest digital canvases. This project is there to motivate creativity when using their newest mouse and give it a test ride, so that you can see how easy and precise it is to use.


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You can save money on every Acura model purchased at Hall Acura Newport News in Virginia. Our friendly salespeople provide the highest levels of customer satisfaction, making us an excellent choice for new Acura cars in Newport News. We have a car lot full of great looking Acura vehicles, including popular models such as the 2014 TL or 2015 MDX, RDX, RLX, ILX and TLX. To begin your new car search, use the Power Search tool below to filter your search by year, make, model and body style.


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At Cincinnati Children's, we recognize the differences and challenges of treating young adults with inflammatory bowel disease, particularly those between the ages of 13 and 18 when self-management is critical. Thanks to our unique diagnostic abilities and pediatric expertise, we are a leading national referral center for complicated inflammatory bowel disease / IBD management.
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To all the Paterno defenders who use the '98 case as 'evidence' of Joe's innocence:
The most likely reason no charges were filed is because that was LOCAL authority investigation - key word being LOCAL, meaning under the influence of PSU football culture.
Paterno defenders keep saying, 'Listen, Jerry was investigated thoroughly in '98 - and no charges were filed...'
But that's not a valid argument.
How else do you explain no charges being filed in spite of a TAPED CONFESSION by Jerry?
How else do you explain the local police abandoning protocol by not opening a crime log, as Freeh pointed out?
The bottom line is this: any time a local agency sided with Jerry, it's likely it had more to do with the machine of PSU football, NOT because he was innocent in '98 or a qualified foster parent.
Finally - even with no charges being filed, Joe should have (a) spoken with Jerry (b) spoken to his assistants and say "we gotta' keep an eye on this guy. - or (c) most humanely, TALKED TO THE CHILD!
To all the Paterno defenders who use the '98 case as 'evidence' of Joe's innocence:
The most likely reason no charges were filed is because that was LOCAL authority investigation - key word being LOCAL, meaning under the influence of PSU football culture.
Paterno defenders keep saying, 'Listen, Jerry was investigated thoroughly in '98 - and no charges were filed...'
But that's not a valid argument.
How else do you explain no charges being filed in spite of a TAPED CONFESSION by Jerry?
How else do you explain the local police abandoning protocol by not opening a crime log, as Freeh pointed out?
The bottom line is this: any time a local agency sided with Jerry, it's likely it had more to do with the machine of PSU football, NOT because he was innocent in '98 or a qualified foster parent.
Finally - even with no charges being filed, Joe should have (a) spoken with Jerry (b) spoken to his assistants and say "we gotta' keep an eye on this guy. - or (c) most humanely, TALKED TO THE CHILD!
as a rationale PSU alum, please take down Joe's statue
and now there's a story (NY Times this morning) that sources close to the Freeh investigation are looking into:
- McQueary getting the job on staff over more qualified candidates BECAUSE of his witnessing the incident - job was payback for keeping his mouth shut.
Not surprising.
And all the posters on here who keep blaming the media for questions about Joe - wake up. The 'blame-the-media game' is a pretty hallow defense at this point.
Time to take down the statue.
Metrix and Dan -
let me be clear again - my summary above is not my work, I'm simply highlighting the key points of the published reports (both here on Pennlive and NBC, which published the infamous '98 police file that the school had been restricting release of).
Metrix - I don't where Chambers' unfavorable Sandusky report went when the child agency investigator Laurie looked at that '98 police file.
I do know - again according to the stories - that it was submitted before Laurie came calling; that Laurie said he never knew of it until last week; and that it was a part of the file - hence it's release now as part of the overall file.
So again - where did it go when the state's child agency (Laurie) investigated?
DAN- I'm not sure I get your question, but we are talking about the Penn State University Police, who work for, ultimately the president of the school - and the BOT.... wow, now I get your question .... WOW!
Metrix - let me be clearer:
the child welfare investigator Jerry Lauro said when he looked at the Penn State police file in '98, the damning report by Chambers (the psychologist who said Jerry was a likely pedophile) was NOT in the file for some reason - even though she (Chambers) had given her report directly to the penn state police.
Lauro said that if Chambers' report had been in the police file, he never would have closed his agency's investigation.
When he finally heard of Chambers' report this week, 14 years later, he said his blood boiled and he didn't know why he never saw her report back in '98.
someone at Penn State (within the police or university) didn't like Chambers' report on Jerry and got another psych "report" that found no problems with Jerry. This second psych report was made by Seasock, who had done extensive work with the Second Mile.
why was Chambers' report pulled from the police file when the child welfare agency came investigating???
Let's boil this story to 1 sentence:
when the child welfare agency came to investigate Sandusky, the psychologist's report saying Sandusky was a "likely" pedophile was not in the file - but the other psychologist's report that said Sandusky was not was in the file . . . and who had the second psychologist who found nothing wrong with Sandusky often work for? The Second Mile.
Sure, the influence and power of the football program was clearly not out of control . . .
I'm not saying I agree. Because logic often has little to do with the NCAA.
But you do have to consider this: if this was a professor and not a football coach, would the alleged atrocities gone on so long?
As for Joe in '98, my paraphrase is pretty accurate; you can google video search it.
I hope everyone sees where this is heading:
a death sentence for the football program, not that that is too important in the context of what we're talking about.
Every story that comes out points to the same Big Picture denominator: there was a collective look-the-other way by too much of the PSU institution and its associated branches.
Now whether Joe knew about '98 is another subject - he was quoted as saying maybe someone said something to him mabout it one time, but he couldn't be sure; I STILL can't believe he would willingly enable this monstrosity.
But what this collective look-the-other-way equals is this: institutional failure in the eyes of the NCAA.
So whether they're right or not, if that's their conclusion, then it's lights out at Beaver Satdium for a season or 2.
Bill - you're missing the point.
The problem is that the '02 incident was many years ago. What I mean is this:
Mike and Joe could both plainly see that nothing had happened to Sandusky. He continued to have free rein of the facilities, attend practices, games, etc. for years after the '02 incident, in the company of children, too.
That's where people are let down. Why was there no follow up by Mike or Joe for YEARS?
Joe could have easily said, "What the heck is going on here? I want an investigation - NOW! Contact the boy in question - NOW!"
But he apparently didn't. It is that lengthy passage of time in which nothing happened that we who love Joe and Penn State have problems with.
Are the morons you signal out (Graham, Gary and Tim) a big-time problem? Heck yes!
But when Mike and Joe see nothing happened to Jerry and accept that, and do not push for any kind of follow-up action for years afterwards, then they too become part of the problem.
This didn't happen last month, when Joe supporters could have said, "Just you wait - if these bozos drop the ball, then Joe will jump in and fix it!"
Unfortunately, there is a decade of proof that says he wouldn't go out of his way for this.... and for the life of me, I can't figure out why.
It is so sad.
it's not hate - it's incomprehension...
Incomprehension that Joe never followed up when he saw nothing had happened to Jerry for a decade. That is where he failed.
You're allowed to applaud Joe's enormous accomplishments for 6 decades and also point out a massive lapse in judgment.
Once again, when it comes to the possibility of child rape, you don't sit back.
it is BIZARRE that a big-time top 10 program historically produced ONE NFL QB in 5 decades under JoePa ....
you would think by sheer luck, we would have had more than 1 regular starter in 5 decades ....
I STILL don't get what happened with Joe's handling of the Sandusky horror - why didn't beat the he$$ out of Jerry?
Early, I wanted to crucify Joe ... Now, I hope there is more to the story. At present it looks like he did the bare minimum.
But I have come around to think he needs to be heard before I write in stone my ultimate feelings for him.
oh - and for the record, he lobbied for Robinson and Clark to start playing QB long before Joe put them in, as Joe has said, over Mills and Morelli ... oh, the waste of talent when I think of how Robinson was used ....
Easy on the hate everyone (including myself).
Was he a good coach? No.
But the man just lost a job and he has a family to support.
And as for giving interviews? I'm glad he says his dad has a story to tell - we all want to hear it.
Good luck, Jay. This will make you a stronger person in the long run.
Davoh is right!!!
Roof's track record is a wreck, plus O line coach was fired by Texas - ugh....
Darren Perry (former PSU and Steelers safety, current asst. coach) = should be new Secondary Coach
Kerry Collins = should be new QB coach
Hoping Ralph Friedgen is OC
Jonesy, he must have come off stronger in person than TV.
On TV, he seemed nervous and as a public speaker, a little stumbling, bumbling, mumbling.
He seems high on likability and fun and decency, light on charisma or "star" quality - which may not be a bad thing, and likely a byproduct of his lack of being a head man.
Good luck, Bill - hope you beat the hell out of Urban and recruit HIS backyard.
He cannot keep any current staff. I hope he doesn't it. Besides their moral failings, their coaching is outdated (3rd and 5? Let's give opposing receivers a 10-yard cushion!)
As for Short and Arrington - cut them some slack.
Their loyalty to Scrap is admirable and I'm sure they were indeed marginalized by Joyner (who did a great job covering up steroids/doping as official U.S. Olympic physician, by the way), even if their views contradict what logically and ethically had to be done (hire outside the immediate PSU family).
My bet is Joyner is letting O'Brien ax the rest of the staff as legal posture to avoid creating liability for the university in future lawsuits. (If they fire staff, they're admitting liability to horror show).
Good luck, Bill; your resume is marginal, but I hope you break the Bellichek trend. We need it ....
what evidence you ask?
first, it's been reported that word about Sandusky's horror was prevalent and increasing in recent years - this has been stated by former players and current professors in an ABC news profile.
second, it's common sense - in a small community people talk. McQuearyy and Bradley were roommates. You would bet that never came up - in a decade?? You are either extremely loyal or dellusional if you think not.
third, Joe had the power and a decade to correct a lack of justice (no action against Jerry after '02), but chose not to press the matter when it would have been very easy for him to have done so.
Look, I love Penn State as much as you, but arguing Joe and others did what's right in this case is a losing proposition.


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How to Help with Nighttime Fears
Preschoolers cling firmly to their beliefs, so dealing with their fears can take considerable patience. It helps to know that although 3- and 4-year-olds are highly susceptible to scary thoughts, the right response on your part can help them work through their anxiety.
A preschooler's fears stem largely from his active imagination and from the difficulty he has distinguishing fantasy from reality. Just as he trusts that Santa will visit on Christmas Eve, he may also believe that monsters lurk under the bed. Three- and 4-year-olds are also making huge cognitive leaps, so they're more aware of danger. Their growing sense of independence heightens this awareness. "As little kids step away from us, they realize how big the world is and how vulnerable they are," says Nancy Jordan, a psychotherapist in Bellevue, Washington. In response, they ricochet from an "I'm a big kid" attitude to one of "Don't leave me; I'm scared.""But It's Real to Me"
By the time she's 5 or 6, your child will understand more clearly what's real and what isn't, and her fears will generally diminish. Until then, you may be tempted to comfort her by stating the obvious -- that monsters aren't real. But this is unlikely to help.
No matter how unrealistic your child's fears may seem to you, they are real to him. "Telling a child that he shouldn't be afraid doesn't make him feel brave," says Marilyn Segal, Ph.D., a evelopmental psychologist at Nova Southeastern University, in Fort Lauderdale. "It only adds a new fear -- that he can't tell you he's afraid because you'll think he's a baby." Similarly, teasing and belittling serve only to keep fears hidden.
Forcing a child to confront her fears is also unproductive, says Madeleine Nathan, Ph.D., a clinical psychologist in Newburyport, Massachusetts. At the same time, she says, letting a child rely on you completely for protection from imaginary terrors won't help her overcome them. If your 4-year-old fears going to the bathroom alone at night, go with her at first, Dr. Nathan suggests. Over the following few weeks or months, ease yourself out of the picture.
Reinforce progress and practice, practice, practice. That's what Carla Mitchell did when her 3-year-old, Kristen, developed an aversion to costumed characters. "It took a lot of visits to Chuck E. Cheese's and amusement parks, but each time, seeing the characters got a little easier," says Mitchell, of Douglasville, Georgia.


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1. run_off - verb
· run away; usually includes taking something or somebody along; "The thief made off with our silver"; "the accountant absconded with the cash from the safe"
Synonym(s): abscond, bolt, absquatulate, decamp, go_off, make_off
Hypernym(s): flee, fly, take_flight
2. run_off - verb
· leave suddenly and as if in a hurry; "The listeners bolted when he discussed his strange ideas"; "When she started to tell silly stories, I ran out"
Synonym(s): run_out, bolt, bolt_out, beetle_off
Hypernym(s): leave, go_forth, go_away
3. run_off - verb
· force to go away; used both with concrete and metaphoric meanings; "Drive away potential burglars"; "drive away bad thoughts"; "dispel doubts"; "The supermarket had to turn back many disappointed customers"
Synonym(s): chase_away, drive_out, turn_back, drive_away, dispel, drive_off
4. run_off - verb
· run away secretly with one's beloved; "The young couple eloped and got married in Las Vegas"
Synonym(s): elope
Hypernym(s): flee, fly, take_flight
5. run_off - verb
· run off as waste; "The water wastes back into the ocean"
Synonym(s): waste
Hypernym(s): run, flow, feed, course
6. run_off - verb
· reproduce by xerography
Hypernym(s): reproduce
7. run_off - verb
· decide (a contest or competition) by a runoff
Hypernym(s): compete, vie, contend
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