text:
|Publication number
|Publication type
|Application number
|Publication date
|Jan 30, 2001
|Filing date
|Jul 12, 1999
|Priority date
|Jul 13, 1998
|Fee status
|Also published as
|Publication number
|James L. Lambert, Mark S. Borchert
|Original Assignee
|California Institute Of Technology, Childrens Hospital Los Angeles
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|BiBTeX, EndNote, RefMan
|Patent Citations (6), Non-Patent Citations (7), Referenced by (138), Classifications (7), Legal Events (8)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims the benefit of U.S. Provisional Application No. 60/092,545, filed Jul. 13, 1998, the disclosure of which is incorporated by reference herein in its entirety.
The invention described herein was made in the performance of work under a NASA contract, and is subject to the provisions of Public Law 96-517 (35 USC 202) in which the Contractor has elected to retain title.
The present invention concerns methods and apparatus for the non-invasive monitoring of blood glucose levels by spectrographic analysis of the aqueous humor in the anterior chamber of the eye.
Non-invasive measurement of blood glucose by any method including optical spectroscopy techniques has remained an elusive target for at least two decades. Blood, tissue, and most excreted fluids contain numerous substances which confound glucose spectral signatures. On the other hand, aqueous humor (AH) filling the anterior chamber of the eye (between the lens and cornea) contains relatively few molecules capable of interfering with the spectroscopic detection of glucose. These are primarily lactate, ascorbate, and urea. This fact, and its optically accessible location behind the cornea, make AH an attractive choice as a site on which to attempt non-invasive analysis of glucose.
Pohjola (Acta Ophthalmologica Suppl. 88, 1-80 (1996)) showed that the ratio of aqueous glucose to plasma glucose in normal euglycemic individuals is related to age and ranges from 0.6 to 0.9. He further showed in seven humans with steady-state hyperglycemia that similar ratios applied. No data exists on the equilibration time of aqueous humor glucose with changes in plasma glucose in humans.
Numerous investigators over the years have suggested that the ratio of aqueous glucose to plasma glucose in the normoglycemic rabbit ranges from 0.42 to 1.01 (S. Pohjola, supra; D. Reddy and V. Kinsey, Arch. Ophthalmol. 63, 715-720 (1960); M. Reim et al., Ophthalmologica 154, 39-50 (1967); W. March et al., Diabetes Care 5, 259 (1982)). It is uncertain whether this variability is normal or could be attributed to differences in glucose measurement techniques, collection techniques, sample storage, and anesthesia. The relationship of aqueous glucose to rising, or falling, plasma glucose has not been previously studied in rabbits.
Cot{acute over (e)} has reviewed the relative strengths and weaknesses of optical glucose sensing techniques (J. Clin. Engineering 22, 253 (1997)). Raman spectroscopy is potentially attractive because it can distinguish glucose in water solutions containing various levels of other optically active metabolites (S. Wang et al., Applied Optics 32, 925 (1993)). Raman spectroscopy measures the shift in the wavelength of incident light as it is scattered by molecules. Any given molecule causes a characteristic shift in the spectrum of scattered light, which is dependent upon its intermolecular and intramolecular bonds. This is in contradistinction to fluorescence, which is caused by changes in electron energy states, and does not shift relative to the wavelength of incident light.
Wicksted et al, (Appl. Sectroscop. 49, 987 (1995)) suggest that the Raman signature for glucose can be identified in aqueous humor samples, and Goetz, et al (IEEE Trans. Biomed. Eng. 42, 728 (1995)), have demonstrated that higher than physiologic levels of glucose can be measured with Raman spectroscopy in water solutions. J. Lambert et al., (LEOS Newsletter 12, 19-22 (1998)) suggest that measurement of glucose at physiologic levels is possible in water solutions containing other analytes normally found in aqueous humor. When solutions containing fluorescent substances are studied, however, the fluorescence signal can overwhelm the relatively weak Raman-shifted signal. This is a potential problem if Raman spectroscopy is applied to aqueous humor, which contains proteins that fluoresce.
U.S. Pat. No. 5,243,983 to Tarr et al. suggest a non-invasive blood glucose measurement system using stimulated Raman spectroscopy. Stimulated Raman spectroscopy requires the use of both a pump and a probe laser beam. The probe laser beam is used to measure the stimulated Raman light at a single wavelength after transmission across the anterior chamber of the eye. This is undesirable, since an optical component contacting the eye is required to direct the beam across the anterior chamber. In addition, use of a single wavelength may limit the ability to measure glucose at physiologic levels within tissue containing many other Raman scattering chemicals.
U.S. Pat. No. 5,433,197 to Stark suggests a non-invasive glucose measurement apparatus that employs broad band infrared light stimulation.
U.S. Pat. No. 5,553,617 to Barkenhagen suggests a non-invasive method for measuring body chemistry from the eye of a subject by measuring a spectral response such as a Raman scattering response. While it is suggested that the invention may be used for medical applications such as the determination of sugar in diabetics, specific details on how this might be accurately carried out are not provided.
U.S. Pat. No. 5,710,30 to Essenpreis suggests a method for measuring the concentration of glucose in a biological sample such as the eye (see FIG. 4 therein) with interferometric measurement procedures.
U.S. Pat. No. 5,666,956 to Buchert et al. suggests that an instrument for the non-invasive measurement of a body analyte can be based on naturally emitted infrared radiation.
In spite of the foregoing efforts, a commercially viable, non-invasive, blood glucose monitor based on a non-invasive analysis of the aqueous humor of the eye has not yet been developed. Difficulties in developing such a device include correlation of aqueous humor glucose levels to blood glucose levels, the difficulty of obtaining accurate measurements, and the need to minimize damaging effects to the eye caused by excessive exposure to light in an instrument that will be used by subjects on a repeated basis. Accordingly, there is a continued need for new methods for the non-invasive analysis of blood glucose levels.
A first aspect of the present invention is a non-invasive method for determining blood level of an analyte of interst, such as glucose. The method comprises:
generating an excitation laser beam (e.g., at a wavelength of 700 to 900 nanometers);
focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor in the anterior chamber is illuminated;
detecting (preferably confocally detecting) a Raman spectrum from the illuminated aqueous humor; and then
determining the blood glucose level (or the level of another analyte of interest) for the subject from the Raman spectrum.
Preferably, the detecting step is followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares or artificial neural network algorithms.
A second aspect of the present invention is an apparatus for the non-invasive determination of the blood level of an analyte of interest such as glucose in a subject.
The apparatus comprises:
a laser for generating an excitation laser beam (e.g., at a wavelength of from 700 to 900 nanometers);
an optical system (e.g., a confocal optical system) operatively associated with said laser for focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor in the anterior chamber is illuminated;
a detector operatively associated with the optical system and configured to detect a Raman spectrum from the illuminated aqueous humor;
preferably a subtraction system, hardware and/or software processor or other suitable means for subtracting a fluorescence spectrum for said aqueous humor from said Raman spectrum to produce a difference spectrum; and
a processor for determining the blood level of the analyte of interest for said subject from the Raman spectrum (or preferably the difference spectrum).
Numerous additional features may be incorporated into the apparatus. The apparatus may include an visual display screen for visually displaying the results of the test to the subject through the same aperture as which the test is conducted. It may include a visual fixation device, also visible through the test aperture, which controls movement of the eye and simultaneously insures that focusing of the laser beam is properly directed into the anterior chamber of the eye. The processor may contain an empirical model of actual testing experience to determine the blood level of the analyte of interest. The apparatus may employ a tunable laser, a plurality of fixed wavelength lasers, or other means for sliding the Raman spectrum passed a plurality of different wavelength detectors to obviate the need for a full grating based Raman spectrometer. A communication line connected to the processor for transmitting the blood level of the analyte of interest to a remote location.
Still other features that can be included in the methods and apparatus described above set forth below.
FIG. 1 illustrates that the broad fluorescence spectrum of aqueous humor can obscure the underlying peaks of interest in the Raman spectrum. Unlike the fluorescence spectrum, the Raman spectra will shift with a change in the excitation wavelength. The raw spectrum of rabbit aqueous humor is shown taken at 2 slightly different wavelengths (top). The difference spectrum (bottom) achieved by subtracting 1 raw spectrum from the other reveals a resultant bipolar Raman signature. Linear and nonlinear multivariate analysis can then be applied.
FIG. 2. The glucose concentration in aqueous humor from 16 rabbits was estimated with Raman spectroscopy and compared to the actual glucose concentration measured with a commercial glucometer. The graph shows the Raman predicted glucose concentration after subtracting fluorescence, and applying a linear partial least square algorithm followed by nonlinear backpropagation with an artificial neural network. This resulted in a high degree of correlation (r2=0.98) of predicted with actual glucose concentration. Applying the partial least squares algorithm alone resulted in lesser correlation (r2=0.90).
FIG. 3. Blood glucose steadily rises at variable rates in rabbits after administration of xylazine anesthesia. On animal (rabbit D, filled diamonds) had little change in blood glucose for unknown reasons.
FIG. 4. Best-fit second-order polynomial curves demonstrate the relationship between aqueous humor glucose and plasma glucose while plasma glucose is rising in 9 animals. Aqueous glucose measurements from the first paracentesis of an eye correlate well with simultaneous plasma glucose (dark curve). When plasma glucose exceeds 200 mg/dL the relationship is nearly linear (dashed line). Aqueous humor glucose exceeds plasma glucose when plasma glucose is less than 200 mg/dL. The relationship of aqueous humor glucose with plasma glucose is different when the aqueous humor sample is obtained as a second paracentesis (light curve) suggesting that the initial paracentesis disrupts normal glucose homeostasis.
FIG. 5 schematically illustrates a first embodiment of an apparatus of the invention.
FIG. 6 schematically illustrates a second embodiment of an apparatus of the invention.
FIG. 7a schematically illustrates the method of sliding Raman spectra features through a particular detector window by changing excitation frequency.
FIG. 7b schematically illustrates an apparatus of the invention that utilizes the method illustrated in FIG. 7a.
FIG. 8 illustrates a visual fixation display that can be utilized in an apparatus of the invention.
FIG. 9 illustrates a visible readout display that can be utilized in an apparatus of the invention.
The term "glucose" as used herein preferably refers to D-glucose.
The term "subject" as used herein refers to both human subjects and animal subjects such as dogs, cats, and rabbits. Animal subjects may be used in the present invention for veterinary purposes. Human subjects are preferred.
The term "processor" as used herein refers to a hardware device, a software or program-implemented device running on a general-purpose computer, or combinations of such hardware and software devices.
The present invention is primarily concerned with the determination of blood glucose levels, and is so explained herein. However, the blood concentration of other Raman-active molecules or analytes such as lactate, urea, ascorbate, drugs, steroids, and alcohol (particularly ethanol) may also be determined by these techniques.
The step of generating an excitation laser beam pulse can be carried out with any suitable laser beam source. The power of the excitation laser beam pulse should be sufficiently low to avoid tissue toxicity, but sufficiently high to provide a measurable Raman signal from the aqueous humor. In general, the laser beam pulse will be at a wavelength of from 700 to 900 nanometers, and more preferably will be at a wavelength of 780 to 860 nanometers to reduce fluorescence, increase tissue penetration, and reduce phototoxicity to the eye. The duration of the pulse will typically be from 1 to 2 seconds to 30 seconds or 60 seconds (i.e., one-half minute to one minute). The total energy of the laser pulse will typically be 200-500 millijoules with instantaneous power not exceeding 30 or 50 milliwatts. The optical components of the apparatus used to carry out the method are preferably configured so that energy on the retina of the eye (as well as other areas susceptible to tissue toxicity, such as the lens and cornea) from the excitation laser beam pulse is not greater than 3000 milliwatts per square centimeter, and more preferably not greater than 2000, 1000 or even 500 milliwatts per square centimeter.
Any source laser that provides the desired frequency output may be employed in carrying out the invention. A distributed feedback laser can be used to reduce instrument size. Tunable or multiple fixed frequency lasers can be combined with bandpass filters (Puppels et al., Applied Spectroscopy 47, 1256-67 (1993)) that select for Raman scattering at wavelengths that provide optimum information for multivariate analysis (this reduces the cost and size of the instrument compared to the use of holographic filters or gratings).
Any suitable detector can be used to detect a Raman spectrum from illuminated aqueous humor. A CCD detector or CCD camera is preferred. The CCD detector preferably has high quantum efficiency in the near infrared range. The high quantum efficiency may be achieved by any suitable means, such as employing a backthinned detector, but one sufficiently thick to reduce etalon effect.
The fluorescence spectrum for the aqueous humor can be subtracted from the Raman spectrum by stimulating the aqueous humor with a second excitation laser light pulse at a wavelength slightly different from that of the first pulse (e.g., up to two nanometers from the first pulse), and then subtracting one spectrum from the other in a processor in accordance with conventional techniques. Such techniques are known. See, e.g., Funfschilling and Williams, Applied Spectroscopy 30, 443 (1976); Baraga et al., Applied Spectroscopy 46, 187 (1992); Wicksted et al., Applied Spectroscopy 49, 987 (1995)). In the alternative, the fluorescence spectrum can be subtracted out through the use of software or other processing techniques. Thus the term "subtraction" as used herein is intended to include techniques such as filtering. While not essential, other potentially interfering spectra or signals such as Raman scattering from the lens, iris, or cornea, can also be filtered or subtracted through a hardware and/or software processor. Water is typically not an issue for Raman spectroscopy, but a water spectrum can be subtracted if desired.
The blood glucose level for the subject is then determined from the difference spectrum by an empirically based model, formula, or matrix of actual subject or sample testing in a hardware and/or software processor. The model can be obtained through linear (e.g., partial least squares) or nonlinear (e.g., artificial neural networks) multivariate analysis. It is important that the training set of Raman spectra used for the multivariate analysis include samples from aqueous humor with a broad range of concentrations of the Raman scattering metabolites. The principal Raman-scattering metabolites (or "Raman active compounds") (glucose, lactate, urea, ascorbate, and any exogeneous compounds or drugs present) preferably should not vary co-linearly with one another among the samples in the training set. The model can be produced with spectra samples obtained from one or more prior subjects, can be produced with spectra samples obtained from the subject from whom the current blood level of the analyte of interest is being determined (in which case that subject would be required to provide a blood sample for determination of the blood concentration of the analyte of interest), or both. Typically, the training set would require at least 20, 25 or 30 Raman spectra samples (and samples of the corresponding blood levels of the analyte of interest) with substantial inter-sample variability in the levels of the major Raman scattering metabolites (e.g., glucose, ascorbate, lactate, urea, and any drugs or exogenous compounds present). The concentration of the analyte of interest (in either the blood or aqueous humor) should vary by at least a factor of 2, 5, 10 or 20 or more from the sample with the lowest concentration to the sample with the highest concentration. This may require development of the model using subjects with multiple different diseases (e.g., renal failure, diabetes, seizures, mitochondrial myopathies, sickle cell disease, heart failure, blood clots, etc.). For human applications, the model may even be determined with spectra samples obtained from animals, particularly primates. The aqueous humor sample may be a natural sample, (human or animal), or may be a man-made or surrogate aqueous humor sample created to mimic natural samples, where the blood level is calculated from a priori knowledge of the relationship between blood levels and aqueous humor levels for the analyte of interest.
For example, where the analyte of interest is glucose, the training set of samples for the empirical model should comprise at least 20, 25 or 30 aqueous humor spectra samples, with the corresponding blood glucose levels, where the principal Raman active compounds in the aqueous humor samples (glucose, ascorbate, lactate, urea, and preferably any exogenous compounds such as drugs) vary substantially non-colinearly among the samples, with either the blood or aqueous humor glucose concentration ranging from 0 or 50 mg/dL to 800 or 1,000 mg/dL, and with there being at least 100, 200, 300 or 400 mg/dL difference in said concentration between the sample with the lowest concentration and the sample with the highest concentration.
A schematic diagram of the general apparatus is depicted in FIG. 5. A tunable, narrow-band laser beam from laser 10 is focused into the anterior chamber 11 of the eye 12 through an objective or ocular lens 13 via lens 15 and filter 16, beam splitter 17, and filter 20. A non-fluorescing objective lens is chosen with suitable numerical aperture (e.g. 0.2-0.5) such that Raman scattering from the aqueous humor is maximized while scattering from adjacent structures (e.g. lens, cornea, and iris) is minimized. The objective lens should have adequate working distance to permit focusing of the laser into the middle of the anterior chamber of the eye without touching the cornea. An integrated fixation target projected from display screen 25 is projected via lens 26 through the same objective lens as the laser, but is focused on the retina of the eye. Focusing this fixation target on the retina simultaneously controls direction and focusing of the laser light in the anterior chamber.
The light collected by the objective lens is directed through holographic notch filters 20, 21 to remove the Raleigh scattered light. The Raman scattered light passes through these filters with minimal attenuation and is focused through a confocal pinhole aperture 22 by lenses 23, 24. The pinhole and the focal point in the anterior chamber of the eye are confocal such that light from adjacent structures in the eye is filtered at this aperture. The pinhole also serves as the entrance aperture to the spectrometer. The spectrometer shown is an imaging spectrograph with a grating 30, lens 31 and a CCD detector array 32. A computer 35 controls the laser 10, the fixation target and readout display 25, and receives data from the CCD detector 32. The architecture of the spectrometer is merely an example of one that is suitable for this application. Many types of spectrographs could be utilized including Fourier transform spectrographs, spectrographs using liquid crystal tunable filters or other tunable elements. Information can be transmitted to a remote source such as a computer, database, remote physician or the like via modem or other connection through a suitable communication line 36 via the internet, world wide web, etc.
The CCD detector in the spectrograph is of a red-shifted, back-thinned, thick epitaxial design such that its sensitivity is optimal in the 700-1100 nanometer spectral region. Other types of very sensitive detectors may be suitable as well.
As noted above, a digital computer processes the output of the CCD detector and controls the frequency and the power of the laser source. The computer switches the frequency of the laser to permit subtraction of fluorescence as described previously. The computer also provides information to a digital display imaged onto the retina. The patient reads the results of the analysis on this display.
Fibers 40, 41 may be used to deliver the laser beam and collect the Raman scattered light as depicted in FIG. 6. (like components in FIGS. 5 and 6 are assigned the same numbers). In this embodiment the confocal aperture is a circular aperture 42 placed on the end of a multimode fiber. As with the pinhole aperture in FIG. 5, the end of said fiber is placed so that it is confocal with the objective lens'focal point in the anterior chamber of the eye. A single mode fiber is used to deliver the laser beam into the anterior chamber. This single mode fiber insures a diffraction limited spot size at the focal point of the objective.
Such a fiber delivery and collection system depicted in FIG. 6 can be connected to an alternative detection system shown in FIG. 7a-b. This alternative detection system will allow for subtraction of the fluorescence spectrum and as well as selected sampling of the frequencies most important for calculation of glucose concentration. Such an alternative detection system would decrease the size and cost of the instrument.
The system depicted in FIG. 7 uses one or more fixed frequency or tunable lasers to illuminate the aqueous humor of the eye using the optical delivery system shown in FIG. 6.
FIG. 7a illustrates that each spectral feature 50 a, 50 b, 50 c of the Raman scattered light is related to the excitation wavelength by a fixed offset, usually expressed in wavenumbers. Changing the excitation wavelength causes the Raman spectra to shift in wavelength, as depicted by the different feature captured in detector range Dλ2 51 based on Raman spectra 52 for excitation frequency Lλ1 as compared to Raman spectra 53 for excitation frequency Lλ2.
An apparatus that takes advantage of the foregoing is schematically illustrated in FIG. 7b. Like components to FIGS. 5 and 6 are assigned like numbers. Laser Drivers and or tuning electronics 60 are operatively associated with a tunable laser or a plurality of fixed wavelength lasers 61, 62, 63. A series of one or more bandpass filter/detector elements 65, 66, 67 operatively associated with amplifiers and analog to digital converter 68 is used to sample the spectrum of the collected light. The center wavelength and bandwidth of each filter is chosen to correspond with a different Raman spectral peak of aqueous humor important for quantification of glucose. If this laser is tunable over a nanometer or so, subtraction of the fluorescent components of the acquired spectrum would also be possible as discussed earlier. Using a laser with a wider tuning range would allow the Raman shifted spectra to be scanned or slid across a smaller number of bandpass filter/detectors. Since semiconductor lasers with extremely wide tuning ranges are not readily available, one could instead use a set of narrowly tunable lasers each with a different center wavelength as the laser means in conjunction with a series of bandpass filter/detectors for this purpose.
Advantageously, the systems described herein may be configured so that optical components need not and do not contact the cornea of the eye during use, which many patients find objectionable (e.g., by providing a suitable monocular eye cup for contacting the orbit around the eye).
The apparatus of the invention can be implemented as a spectrometer base unit attached by a fiberoptic cable to an ocular probe, or as a single integrated unit including foreoptics, spectrometer, detector, computer and display.
As noted above, a visual fixation target such as a mirror, LED or the like can be built into the optical apparatus to facilitate focusing of the excitation light into the anterior chamber and maintain stability of the eye. In the embodiment of FIGS. 5-7, a display screen such as a liquid crystal display is employed. As shown in FIG. 8, a blinking fixation target in the form of an hourglass 70 can be displayed, focused on the retina, during acquisition of the spectra by the apparatus. This will help optimize the Raman signal from the aqueous humor and reduce light exposure to other structures of the eye. The fixation target is active and displayed during the time that the laser beam is active and illuminating the subject's aqueous humor. As shown in FIG. 9, a visible indication of the results of the test in the form of alphanumeric indicia 71 (or other suitable form, such as a graphical display) can be displayed on the same screen immediately after the acquisition step. The indicia of FIG. 9 provide a readout for all of the principal Raman-active compounds of the aqueous humor, but only one need be so displayed.
The instrument of the invention can be operatively associated with a patient's insulin pump (for D-glucose) or to a dialysis machine (for urea) by electrical or fiber optic lines, radio frequency transmitters and receivers or the like to provide information on the appropriate analyte that can then be used to control that apparatus and increase or decrease the output of the insulin pump in response to blood glucose levels, or to regulate the dialysis machine.
In telemedicine applications, the instrument of the invention can be conveniently operatively associated with a remote read-out terminal through a computer, modem, internet connection or other communication line with any any suitable means (such as an electrical or fiber optic lines, radio frequency transmitters and receivers, etc.) to provide information on the blood analyte to a remote physician or medical provider (e.g., through the internet or world wide web).
The present invention is explained in greater detail in the following nonlimiting Examples, in which "μL" means microliters; "d L" means deciliters, "mW" means milliwatts, "nm" means nanometers, "Kg" means kilograms, "J" means Joules, "cm2" means square centimeters, and temperatures are given in degrees Centigrade.
Aqueous humor was obtained from sixteen New Zealand white rabbits within one minute of sacrifice by other investigators. These animals had experienced experimental myocardial infarction 48 hours prior to euthanasia. They were sacrificed by rapid exsanguination under ketamine and xylazine anesthesia. Aqueous humor samples were kept frozen until glucose levels could be measured and Raman spectroscopy performed. Glucose concentration was measured with a commercial glucometer (Glucometer Elite, Bayer, Elkhart, Ind., USA) and confirmed against concentration standards. Each measurement was repeated, and the average measurement was considered actual glucose concentration.
Samples were placed in conical quartz cuvettes designed to hold a volume of 80 μL and permit direct optical access to the solution by the spectrometer without traversing glass walls or coverslips.
Raman spectroscopy was performed with a f/1.8 holographic imaging spectrograph (Kaiser Optical Systems, Ann Arbor, Mich., USA) attached to an Olympus BX60 microscope with 10� objective. Data were collected using a Princeton Instruments (Trenton, N.J., USA) camera with a 1024�256 CCD array (EEV, United Kingdom) cooled to −80� C. with liquid nitrogen. Illumination of the sample through the microscope objective was achieved with a Ti:Sapphire laser (Spectra Physics 3900S, Mountain View, Calif., USA) pumped by an argon laser (Spectra Physics 2010E). Spectrographic data was integrated while the sample was illuminated at a wavelength of 785.0 nm (30 mW) for 10 seconds. This was then repeated at a wavelength of 787.2 nm.
The integrated spectra at the two slightly different wavelengths were then subtracted from one another. This effectively eliminates the broadband fluorescence, which does not shift relative to the excitation wavelength. It leaves the Raman-shifted spectra appearing as a bipolar pattern. (FIG. 1)
Multivariate analysis of the spectra was accomplished using Holograms (Princeton Instruments, Trenton, N.J.) and Grams (Galactic Industries, Salem, N. H., USA) software packages. Thirty-two aqueous humor samples (from sixteen rabbits) were evaluated using a "round robin" approach to iteratively group all but one of the samples into a training set. Hence, the system trains on all but one of the samples, estimates the glucose level in that sample, then rotates the test sample into the training set. This cycle is repeated until all samples have served as an unknown test sample.
We subsequently employed a backpropagation neural network (D. Rumelhart et al., Nature 323, 533 (1986)) to determine if a nonlinear regression method would better predict the glucose concentration from the Raman spectra of aqueous humor. Such a model may compensate for as yet unknown interactions between analytes in aqueous humor. We employed a two-layer backpropagation neural network (NeuralWare, Inc., Pittsburgh, Pa., USA) using a sigmoidal function as the nonlinear element. Factors derived from the partial least squares algorithm served as the inputs to the neural network. Raw spectral data could have been used but would have required a prohibitively large training set. As in the linear regression preformed earlier, round robin training and testing was utilized. During training, the neural network's weights were adjusted to minimize the total squared error between the actual glucose concentration and the predicted glucose concentrations. Each sample was tested using a neural network trained on the remaining 31 samples.
Nine female New Zealand white rabbits were used for this part of the study. They were anesthetized with ketamine (50 mg/kg) and xylazine (7.5 mg/kg) given as a single intramuscular injection. Xylazine blocks release of insulin from the pancreas and causes blood glucose to rise (K. Chalabi et al., Ophthalmic Res. 19, 289 (1987); J. Arnbjerg et al., Ophthalmic Res. 22, 265 (1990)).
Blood samples were taken from the central ear arteries at various times following the injection of anesthetic once the animals were adequately anesthetized. Whole blood was immediately measured for glucose concentration with a commercial glucometer (Glucometer Elite, Bayer). In most instances two measurements were made. The average measurements are reported. If the measurements differed by more than 20%, a third measurement was made. If one measurement differed by more than 20% from the mean, it was discarded. In instances when blood glucose concentration appeared stable, occasionally only one measurement was made.
At various times after induction of anesthesia, samples of aqueous humor were taken. This was done by paracentesis with a 25-gauge needle through clear cornea near the limbus after administration of proparacaine eye drops. Aqueous humor glucose concentration was measured with the glucometer in a manner similar to the blood.
In rabbits, there is massive breakdown of the blood-aqueous barrier after a single paracentesis of the anterior chamber of the eye (W. Unger et al., Exp. Eye Res. 20, 255 (1975)). The aqueous humor becomes too viscous for repeat paracentesis for at least 30 minutes. Consequently, our results are reported for the first paracentesis of an eye. In a few instances, however, a second paracentesis was made an hour later to assess how the breakdown of the blood-aqueous barrier may have affected the correlation of aqueous glucose with plasma glucose.
Average blood glucose concentrations for each animal were plotted against time after anesthetic injection. Since it was impossible to obtain blood samples simultaneous with aqueous humor samples, a best-fit second-order polynomial was calculated for each animal. This was used to calculate the blood glucose concentration at the time that the aqueous humor sample was taken. Aqueous humor glucose concentration was then plotted against the calculated simultaneous blood glucose concentration for all animals. DeltaGraph software (Delta Point, Inc., Monterey, Calif., USA) was used for all statistical calculations.
The raw spectra of rabbit aqueous humor show broad fluorescence peaks that obscure the underlying Raman signature. (FIG. 1) When the spectra from the two slightly different wavelengths are subtracted, one from the other, the Raman shifted spectra become apparent as bipolar peaks.
Actual aqueous humor glucose concentration, measured by the glucometer, ranged from 37 to 323 mg/dL in the thirty-two samples. Multivariate analysis of the raw spectra from these samples with the partial least squares algorithm revealed fair correlation (r2=0.76) between the predicted aqueous humor glucose concentration and the actual concentration. Multivariate analysis of the subtracted spectra from these samples with the partial least squares algorithm resulted in improved correlation (r2=0.90) between the predicted aqueous humor glucose concentration and the actual concentration. When backpropagation with an artificial neural network is further applied to the data, correlation is excellent (r2=0.98). (FIG. 2).
The rate of rise of blood glucose after xylazine injection is highly variable from animal to animal. (FIG. 3) In fact, in one rabbit there was little change in the blood glucose concentration over time.
If only samples taken in the first fifteen minutes after anesthetic injection are considered, aqueous humor glucose concentration is higher than blood glucose concentration (207�28 mg/dL for aqueous humor; 135�27 mg/dL for blood). When calculated blood glucose rises above 200 mg/dL, simultaneous aqueous humor glucose parallels blood glucose nearly linearly [aqueous humor glucose=1.18 (blood glucose)−72.7; r2=0.88]. (FIG. 4)
The number of aqueous humor samples from second paracenteses was insufficient to draw conclusions about their significance. They did not appear, however, to correlate well with aqueous humor glucose levels from initial paracenteses. (FIG. 4)
These data indicate that the baseline ratio of aqueous humor glucose to blood glucose in rabbits is approximately 1.5. (It may actually be higher than this as a true baseline was not obtained, and the blood glucose levels were likely elevated by the time the first samples were obtained, even in the first 15 minutes after injection.) This is much higher than in humans and higher than in previous reports on rabbits. All previous reports on rabbits, however, were prior to recognition of the hyperglycemic effect of xylazine anesthesia, yet many of them used xylazine anesthesia. In addition, most previous reports assumed that the rabbits were at steady-state euglycemia, without actually confirming that this was the case. These facts may account for some of the highly variable results in previous reports.
These data also demonstrate that aqueous humor glucose in the rabbit responds almost immediately once blood glucose exceeds 200 mg/dL. The relationship of aqueous humor glucose to blood glucose is nearly linear while blood glucose is rising above 200 mg/dL. Below that level, aqueous humor glucose appears stable. What happens to aqueous humor glucose when blood glucose is clamped at a hyperglycemic level, or when blood glucose concentration drops has yet to be determined. Nonetheless, equilibration of aqueous humor glucose with blood glucose probably occurs within minutes in rabbits. If rapid equilibration of aqueous humor glucose also occurs in humans, it could serve as an excellent substrate for non-invasive glucose monitoring.
Previous investigators have found no breakdown in the blood-aqueous barrier of albino rabbits exposed to infrared radiation with energy densities up to 106 J/cm (D. Reddy, supra; G. Peyman et al., Exp. Eye Res. 42, 249 (1986); T. Kurnik et al., Inv. Ophthalmol. Vis. Sci. 30, 717 (1989)). Infrared energy densities as low as 44 J/cm2 may be sufficient to breakdown the blood-aqueous barrier in pigmented rabbits, however. This is still substantially higher than the energy density that would need be applied with the Raman technique disclosed herein.
The blood-brain and blood-aqueous barriers block passage of large molecules into the cerebrospinal fluid or aqueous humor. Many drugs and disease processes result in disruption of both the blood-aqueous barrier and the blood-brain barrier. In the case of such drugs or disease processes, disruption of the blood-brain barrier can be inferred from breakdown of the blood-aqueous barrier. Breakdown of the blood-aqueous barrier can be measured by measuring the protein content of the aqueous humor or by measuring the concentration of other substances (e.g., drugs) within the aqueous humor. Such substances may be quantifiable by Raman spectroscopy and the protein can be calculated from the fluorescence spectrum since the fluorescence spectrum is largely generated by protein. Consequently, the device disclose herein for measuring glucose and other Raman scattering metabolites in the eye can be used for measuring the integrity of the blood-aqueous and blood-brain barriers.
Raman scattering molecules of different sizes that do not normally cross the blood-aqueous or blood-brain barrier could be administered to a patient intravenously. The presence of these molecules is then quantified by Raman spectroscopy of the anterior chamber of the eye. This can be used to determine the size of molecules which pass through the blood aqueous barrier. The amount of fluorescence that is subtracted to reveal the Raman spectra of these substances, with the device disclosed herein would reflect the passage of natural proteins through the blood-aqueous and blood brain barriers.
Therapeutic drugs can also be measured to determine their effectiveness in crossing the blood-aqueous or blood-brain barrier.
The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.
|Cited Patent
|Filing date
|Publication date
|Dec 14, 1990
|Sep 14, 1993
|Georgia Tech Research Corporation
|Non-invasive blood glucose measurement system and method using stimulated raman spectroscopy
|Sep 4, 1992
|Jul 18, 1995
|Stark; Edward W.
|Non-invasive glucose measurement method and apparatus
|Dec 17, 1993
|Jul 16, 1996
|Boehringer Mannheim Gmbh
|Device for the in vivo determination of an optical property of the aqueous humour of the eye
|Jan 20, 1995
|Sep 10, 1996
|Hughes Aircraft Company
|Noninvasive method and apparatus for determining body chemistry
|May 20, 1996
|Sep 16, 1997
|Buchert; Janusz Michal
|Instrument and method for non-invasive monitoring of human tissue analyte by measuring the body's infrared radiation
|Apr 26, 1995
|Jan 20, 1998
|Boehringer Mannheim Gmbh
|Method and apparatus for determining glucose concentration in a biological sample
|Berger et al.; Feasibility of Measuring Blood Glucose Concentration by Near-Infrared Raman Spectroscopy, Abstract, Spectrochim Acta A Mol Biomol Spectrosc, 53A(2):287-292 (Feb. 1997).
|Berger, A.J. et al.; Rapid, Noninvasive Concentration Measurements of Aqueous Biological Analytes by Near-Infrared Raman Spectroscopy, Abstract, Applied Optics, 35(1):209-12 (Jan. 1, 1996).
|Borchert et al., A Noninvasive Glucose Monitor: Preliminary Results in Rabbits, Diabetes Technology& Therapeutics1(2): 145-151 (1999).
|Erckens et al.; Raman Spectroscopy for Non-Invasive Characterization of Ocular Tissue: Potential for Detection of Biological Molecules, Abstract, J. of Raman Spectroscopy, 28(5):293-9 (May 1997).
|Schulze HG et al., Artificial Neural Network and Classical Least-Squares Methods for Neurotransmitter Mixture Analysis, Abstract, J. Neurosci Methods, 56(2):155-167 (Feb. 1995).
|Wang et al,; Analysis of Metabolites in Aqueous Solutions by Using Laser Raman Spectroscopy, Applied Optics, 32(6):925-929 (Feb. 20, 1993).
|Wicksted et al., Raman Spectroscopy Studies of Metabolic Concentrations in Aqueous Solutions and Aqueous Humor Specimens, Applied Spectroscopy, 49(7):987-993 (1995).
|Citing Patent
|Filing date
|Publication date
|Feb 23, 2001
|Apr 8, 2003
|Marcio Marc Abreu
|Noninvasive measurement of chemical substances
|Aug 10, 2000
|Apr 15, 2003
|Euro-Celtique, S.A.
|Automated system and method for spectroscopic analysis
|Jan 9, 2001
|Jun 3, 2003
|Childrens Hospital Los Angeles
|Assessing blood brain barrier dynamics or identifying or measuring selected substances or toxins in a subject by analyzing Raman spectrum signals of selected regions in the eye
|Aug 17, 2001
|Jan 6, 2004
|Euro-Celtique, S.A.
|Near infrared blood glucose monitoring system
|Aug 27, 2001
|Mar 16, 2004
|Array Bioscience Corporation
|Systems and methods for filter based spectrographic analysis
|Nov 18, 1999
|Apr 13, 2004
|The United States Of America
|Method for non-invasive identification of individuals at risk for diabetes
|Aug 15, 2003
|May 3, 2005
|Fovioptics Inc.
|Non-invasive measurement of blood analytes using photodynamics
|Aug 15, 2003
|May 17, 2005
|Fovioptics Inc.
|Non-invasive psychophysical measurement of glucose using photodynamics
|Mar 25, 2003
|Nov 1, 2005
|Childrens Hospital Los Angeles
|Identifying or measuring selected substances or toxins in a subject using resonant raman signals
|Feb 17, 2006
|Feb 13, 2007
|Axsun Technologies, Inc.
|Method and system removing fluorescence and other slowly varying baseline in Raman spectra
|Apr 22, 2003
|Mar 6, 2007
|Marcio Marc Abreu
|Apparatus and method for measuring biologic parameters
|Jul 5, 2002
|Mar 20, 2007
|Cognis Corporation
|On-site analysis system with central processor and method of analyzing
|Sep 9, 2004
|May 8, 2007
|Kitchener Clark Wilson
|Apparatus and method for noninvasive monitoring of analytes in body fluids
|Oct 8, 2003
|Jun 19, 2007
|Brian Yen
|Apparatus and method for pattern delivery of radiation and biological characteristic analysis
|Aug 20, 2004
|Sep 4, 2007
|C8 Medisensors Inc.
|Measuring analytes from an electromagnetic spectrum using a wavelength router
|Jul 21, 2005
|Oct 2, 2007
|C8 Medisensors Inc.
|Measuring spectral lines from an analyte using multiplexed holograms and polarization manipulation
|Aug 1, 2002
|Dec 11, 2007
|Glucovista, Llc
|Non-invasive glucose meter
|Jun 7, 2005
|Feb 12, 2008
|Chem Image Corporation
|Non-invasive biochemical analysis
|Mar 25, 2003
|Jul 8, 2008
|Childrens Hospital Los Angeles
|Assessing blood brain barrier dynamics or identifying or measuring selected substances, including ethanol or toxins, in a subject by analyzing Raman spectrum signals
|Apr 25, 2003
|Jul 22, 2008
|Marcio Marc Abreu
|Apparatus and method for noninvasive measurement of analytes from the conjunctiva using mid-infrared radiation
|Oct 11, 2007
|Jan 5, 2010
|Glucovista, Llc
|Non-invasive glucose meter
|Mar 16, 2006
|Jan 26, 2010
|Eyesense Ag
|Apparatus for measuring blood glucose concentrations
|Nov 20, 2006
|Feb 2, 2010
|Marcio Marc Abreu
|Apparatus for physical measurements of the eye
|May 30, 2003
|Jul 13, 2010
|Marcio Marc Abreu
|Device for generating a detectable signal based upon antibody/antigen interaction
|Oct 20, 2004
|Aug 3, 2010
|Lein Applied Diagnostics Limited
|Ocular property measuring apparatus and method therefor
|Aug 25, 2005
|Oct 5, 2010
|Panasonic Electric Works Co., Ltd.
|Method of preparing calibration curve for quantitative analysis of in-vivo component, and quantitative analyzer using the calibration curve
|Jun 30, 2006
|Oct 5, 2010
|Marcio Marc Abreu
|Contact lens for collecting tears and detecting analytes for determining health status, ovulation detection, and diabetes screening
|Apr 21, 2005
|Oct 19, 2010
|University Of Virginia Patent Foundation
|Method, system and computer program product for evaluating the accuracy of blood glucose monitoring sensors/devices
|Jul 29, 2008
|Sep 6, 2011
|Lein Applied Diagnostics
|Optical alignment apparatus and method therefor
|Nov 24, 2004
|Dec 13, 2011
|Lein Applied Diagnostics Limited
|Extended focal region measuring apparatus and method
|Oct 24, 2006
|May 8, 2012
|Marcio Marc Abreu
|Apparatus and method for measuring biologic parameters
|Feb 11, 2008
|Jul 10, 2012
|Glucovista Inc.
|Apparatus and method using light retro-reflected from a retina to non-invasively measure the blood concentration of a substance
|Jun 26, 2007
|Sep 25, 2012
|Non-invasive blood constituent measuring instrument and measuring method
|Oct 24, 2006
|Dec 11, 2012
|Marcio Marc Abreu
|Apparatus and method for measuring biologic parameters
|Apr 27, 2006
|Jan 15, 2013
|Massachusetts Institute Of Technology
|Raman spectroscopy for non-invasive glucose measurements
|Feb 11, 2008
|Jan 29, 2013
|Glucovista, Inc.
|Apparatus and method for non-invasive measurement of the concentration of a substance in subjects blood
|Dec 2, 2009
|Jan 29, 2013
|Gluco Vista, Inc.
|Non-invasive glucose meter
|Feb 11, 2008
|Sep 10, 2013
|ChemImage Technologies, LLL
|Invasive chemometry
|Jul 29, 2008
|Apr 15, 2014
|Lein Applied Diagnostics
|Optical measurement apparatus and method therefor
|Mar 5, 2007
|May 13, 2014
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Jul 8, 2010
|Jul 8, 2014
|Geelux Holdings, Ltd.
|Device for generating a detectable signal based upon concentration of at least one substance
|Dec 10, 2012
|Sep 16, 2014
|Geelux Holdings, Ltd.
|Thermal imaging system
|Nov 21, 2012
|Sep 23, 2014
|Folim G. Halaka
|Non-invasive reagentless glucose determination
|Feb 26, 2004
|Sep 30, 2014
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Jun 13, 2008
|Dec 16, 2014
|Geelux Holdings, Ltd.
|Noninvasive measurement of chemical substances
|Mar 5, 2013
|Mar 17, 2015
|Industrial Technology Research Institute
|System and method for measuring the rotation angle of optical active substance
|May 12, 2014
|Apr 21, 2015
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Feb 9, 2009
|May 5, 2015
|Lein Applied Diagnostics
|Measurement apparatus and method therefor
|Jul 24, 2006
|Aug 11, 2015
|Massachusetts Institute Of Technology
|Intrinsic Raman spectroscopy
|May 7, 2012
|Sep 1, 2015
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Feb 13, 2015
|Apr 5, 2016
|Geelux Holding, Ltd.
|Apparatus and method for measuring biologic parameters
|Sep 5, 2014
|Jul 26, 2016
|Geelux Holdings, Ltd.
|Thermal imaging system
|Apr 15, 2015
|Aug 9, 2016
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Jan 12, 2016
|Sep 13, 2016
|Zyomed Corp.
|Systems and methods for synthesis of zyotons for use in collision computing for noninvasive blood glucose and other measurements
|Jul 16, 2015
|Sep 20, 2016
|Geelux Holdings, Ltd.
|Apparatus and method for measuring biologic parameters
|Jan 12, 2016
|Sep 20, 2016
|Zyomed Corp.
|Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
|Mar 25, 2016
|Sep 20, 2016
|Zyomed Corp.
|Systems and methods for control of illumination or radiation collection for blood glucose and other analyte detection and measurement using collision computing
|Mar 25, 2016
|Sep 27, 2016
|Zyomed Corp.
|Systems and methods for blood glucose and other analyte detection and measurement using collision computing
|Sep 29, 2015
|Oct 4, 2016
|Zyomed Corp.
|Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing
|Jan 12, 2016
|Oct 4, 2016
|Zyomed Corp.
|Systems and methods for collision computing for detection and noninvasive measurement of blood glucose and other substances and events
|Jan 12, 2016
|Oct 4, 2016
|Zyomed, Corp.
|Systems and methods for generating and using projector curve sets for universal calibration for noninvasive blood glucose and other measurements
|Aug 11, 2016
|Jan 31, 2017
|Zyomed Corp.
|Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing
|Aug 10, 2016
|Apr 4, 2017
|Zyomed Corp.
|Systems and methods for measurement of heart rate and other heart-related characteristics from photoplethysmographic (PPG) signals using collision computing
|Dec 27, 2013
|May 30, 2017
|Taiwan Biophotonic Corporation
|Apparatus for non-invasive glucose monitoring
|Sep 23, 2014
|Jul 4, 2017
|Folim G. Halaka
|Cancer cell detection using dielectrophoretic dynamic light scattering (DDLS) spectroscopy
|Aug 8, 2001
|Sep 19, 2002
|Kreimer David I.
|Amplification of analyte detection by substrates having particle structures with receptors
|Mar 15, 2002
|Oct 17, 2002
|Kreimer David I.
|Enhancing surfaces for analyte detection
|Jul 8, 2002
|Apr 10, 2003
|Abreu Marcio Marc
|Method and apparatus for signal transmission and detection using a contact device
|Jul 5, 2002
|Jul 17, 2003
|Kent J. Thomas
|Extensible modular communication executive with active message queue and intelligent message pre-validation
|Jul 5, 2002
|Aug 14, 2003
|Lundstedt Alan P.
|On-site analysis system with central processor and method of analyzing
|Nov 18, 2002
|Dec 18, 2003
|Kreimer David I.
|Beads having identifiable Raman markers
|Mar 25, 2003
|Jan 29, 2004
|Lambert James L.
|Assessing blood brain barrier dynamics or identifying or measuring selected substances, including ethanol or toxins, in a subject by analyzing Raman spectrum signals
|Nov 14, 2002
|Feb 5, 2004
|Kreimer David I.
|Biochips for characterizing biological processes
|Apr 25, 2003
|Feb 26, 2004
|Abreu Marcio Marc
|Noninvasive measurement of chemical substances
|Apr 22, 2003
|Mar 25, 2004
|Abreu Marcio Marc
|Apparatus and method for measuring biologic parameters
|Aug 15, 2003
|May 6, 2004
|Rice Mark J.
|Non-invasive psychophysical measurement of glucose using photodynamics
|Oct 8, 2003
|May 6, 2004
|Brian Yen
|Apparatus and method for pattern delivery of radiation and biological characteristic analysis
|Mar 25, 2003
|Jul 1, 2004
|Lambert James L.
|Identifying or measuring selected substances or toxins in a subject using resonant raman signals
|Aug 15, 2003
|Jul 29, 2004
|Fovioptics, Inc.
|Non-invasive measurement of blood analytes using photodynamics
|Apr 14, 2004
|Nov 4, 2004
|Burd John F.
|Method and instruments for non-invasive analyte measurement
|Feb 26, 2004
|Dec 2, 2004
|Abreu Marcio Marc
|Apparatus and method for measuring biologic parameters
|Aug 12, 2004
|Dec 23, 2004
|Jonathan Gerlitz
|Non-invasive glucose-meter
|Jun 8, 2004
|Jan 13, 2005
|Woods Joe W.
|Non-invasive measurement of blood glucose using retinal imaging
|Jan 27, 2004
|Feb 10, 2005
|Euro-Celtique, S.A.
|Wireless blood glucose monitoring system
|Nov 26, 2003
|Feb 24, 2005
|Skymoon Research And Development, Llc
|Optical vivo probe of analyte concentration within the sterile matrix under the human nail
|Apr 14, 2004
|Apr 21, 2005
|Burd John F.
|Methods for non-invasive analyte measurement from the conjunctiva
|Aug 20, 2004
|Jun 9, 2005
|Jan Lipson
|Measuring analytes from an electromagnetic spectrum using a wavelength router
|Feb 20, 2004
|Aug 4, 2005
|Q Step Technologies, Llc
|Noninvasive measurement system
|Feb 24, 2004
|Aug 25, 2005
|Skymoon Research & Development, Llc
|Anti-stokes raman in vivo probe of analyte concentrations through the human nail
|Mar 25, 2003
|Mar 23, 2006
|Ken-Ichi Yamakoshi
|Non-invasive blood component value measuring instrument and method
|Aug 25, 2005
|Mar 23, 2006
|Matsushita Electric Works, Ltd.
|Method of preparing calibration curve for quantitative analysis of in-vivo component, and quantitative analyzer using the calibration curve
|Mar 16, 2006
|Aug 10, 2006
|March Wayne F
|Apparatus for measuring blood glucose concentrations
|Feb 17, 2006
|Sep 7, 2006
|Axsun Technologies, Inc.
|Method and system removing fluorescence and other slowly varying baseline in Raman spectra
|May 24, 2006
|Oct 5, 2006
|Oculir, Inc.
|Methods for non-invasive analyte measurement
|Jul 26, 2006
|Nov 16, 2006
|Oculir, Inc.
|Non-Invasive Analyte Measurement Device for Measuring Tears and Other Ocular Elements Using Electromagnetic Radiation and Method of Using the Same
|Jun 7, 2005
|Dec 7, 2006
|Chemlmage Corporation
|Non-invasive biochemical analysis
|Nov 3, 2005
|Dec 7, 2006
|Chemimage Corporation
|Invasive chemometry
|Jun 30, 2006
|Jan 18, 2007
|Abreu Marcio M
|Contact lens for collecting tears and detecting analytes for determining health status, ovulation detection, and diabetes screening
|Jul 21, 2005
|Jan 25, 2007
|Jan Lipson
|Measuring spectral lines from an analyte using multiplexed holograms and polarization manipulation
|Jul 24, 2006
|Mar 1, 2007
|Kate Bechtel
|Intrinsic Raman spectroscopy
|Apr 27, 2006
|Mar 15, 2007
|Martin Hunter
|Raman spectroscopy for non-invasive glucose measurements
|Oct 24, 2006
|May 10, 2007
|Abreu Marcio M
|Apparatus and method for measuring biologic parameters
|Nov 24, 2004
|May 31, 2007
|Daly Daniel J
|Extended focal region measuring apparatus and method
|Feb 15, 2007
|Jun 21, 2007
|Lundstedt Alan P
|On-site analysis system with central processor and method of analyzing
|Mar 12, 2007
|Jun 28, 2007
|Brian Yen
|Apparatus and Method for Pattern Delivery of Radiation and Biological Characteristic Analysis
|Mar 5, 2007
|Sep 20, 2007
|Abreu Marcio M
|Apparatus and method for measuring biologic parameters
|Apr 21, 2005
|Oct 4, 2007
|University Of Virginia Patent Foundation
|Method, System and Computer Program Product for Evaluating the Accuracy of Blood Glucose Monitoring Sensors/Devices
|Aug 17, 2007
|Dec 6, 2007
|C8 Medisensors Inc.
|Calibrating measurements of analyte concentrations in solvents from an electromagnetic spectrum
|Aug 10, 2007
|Jan 10, 2008
|Oculir, Inc.
|Methods for non-invasive analyte measurement
|Jun 26, 2007
|Jan 31, 2008
|Tyt Institute Of Technology Corporation
|Non-invasive blood constituent measuring instrument and measuring method
|May 28, 2004
|Feb 7, 2008
|Zeller Philipp N
|Measuring Blood Glucose Concentration
|Oct 11, 2007
|May 15, 2008
|Gluco Vista
|Non-invasive glucose meter
|Feb 11, 2008
|Sep 18, 2008
|Chemimage Corporation
|Invasive chemometry
|Mar 8, 2007
|Jan 29, 2009
|Masahiko Shioi
|Instrument for measuring concentration of living body ingredient
|Jun 13, 2008
|Feb 5, 2009
|Marcio Marc Abreu
|Noninvasive measurement of chemical substances
|Oct 24, 2006
|Apr 23, 2009
|Marcio Marc Abreu
|Apparatus and method for measuring biologic parameters
|Dec 2, 2009
|Jun 17, 2010
|Glucovista, Llc
|Non-invasive glucose meter
|Jan 24, 2010
|Jul 22, 2010
|Eyesense Ag
|Apparatus for measuring blood glucose concentrations
|Feb 1, 2010
|Aug 5, 2010
|Cole Steven W
|Feedback sensor for real-time management of sickle cell disease
|Jul 29, 2008
|Aug 19, 2010
|Richard Holley
|Optical Apparatus for Measuring a Physiological Property of a Body Part and Method Therefore
|Jul 29, 2008
|Sep 2, 2010
|Austen Hearn
|Optical Alignment Apparatus and Method Therefor
|Jul 8, 2010
|Feb 3, 2011
|Marcio Marc Abreu
|Contact lens for collecting tears and detecting at least one analyte
|Jul 8, 2010
|Feb 17, 2011
|Marcio Marc Abreu
|Device for generating a detectable signal based upon concentration of at least one substance
|Jan 5, 2012
|Jul 12, 2012
|Maynard John D
|Determination of a Measure of a Glycation End-Product or Disease State Using Tissue Fluorescence of Various Sites
|Dec 17, 2012
|Dec 4, 2014
|Laser scanning method for measuring in vivo substances
|Aug 23, 2004
|May 5, 2010
|Measuring analytes from an electromagnetic spectrum using a wavelength router
|May 23, 2011
|Sep 21, 2011
|Zoom multi-channel microscopic imaging system of eye retina
|Dec 30, 2002
|Dec 1, 2004
|The University of Utah Research Foundation
|Method and apparatus for raman imaging of macular pigments
|Dec 30, 2002
|Apr 5, 2006
|Univ Utah Res Found
|Method and apparatus for raman imaging of macular pigments
|Mar 25, 2003
|Jan 19, 2005
|Yamakoshi, Ken-ichi
|Noninvasive blood component value measuring instrument and method
|Mar 25, 2003
|May 2, 2007
|Tyt Inst Of Technology Corp
|Noninvasive blood component value measuring instrument and method
|Jan 23, 2004
|Nov 2, 2005
|Research Foundation of the city University of New York
|Strokes shift emission spectroscopy for detection of disease and physiological state of specimen
|Jan 23, 2004
|Feb 27, 2008
|Res Foundation Of City Univers
|Strokes shift emission spectroscopy for detection of disease and physiological state of specimen
|Aug 23, 2004
|Jun 7, 2006
|Measuring analytes from an electromagnetic spectrum using a wavelength router
|Aug 23, 2004
|Jun 2, 2010
|C8 Medisensors Inc
|Measuring analytes from an electromagnetic spectrum using a wavelength router
|Aug 20, 2001
|Sep 6, 2002
|Marcio Marc Abreu
|Noninvasive measurements of chemical substances
|Oct 27, 2003
|May 21, 2004
|Brian Yen
|Apparatus and method for pattern delivery of radiation and biological characteristic analysis
|Jul 22, 2005
|Feb 1, 2007
|C8 Inc
|Measuring spectral lines from an analyte using multiplexed holograms and polarization manipulation
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Nov 8, 1999
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Subjects taught at LSE | Services and divisions (administration)
All research groups | Research subject areas
Hazel Johnstone MBE
Departmental Manager
Louisa started her ESRC-funded PhD at the Gender Institute in 2014, exploring the process of unionization of domestic workers in Brazil and their struggle to be recognised as workers. In this projects, she pays particular attention to the intersection of gender, race and class in the construction of social hierarchies and the ways in which it determines the value of women's labour. Her research interests include social movements, industrial relations, feminist political economy, postcoloniality, Brazilian and Latin American politics. She is native speaker in French and Portuguese and fluent in Spanish.
Louisa was awarded her MSc in Gender Research at the GI in 2013 with distinction. She also holds an MSc in Comparative Politics - Latin America (2011) and a BSc in Political Science (2009) from Science Po Paris. Her professional experience includes policy analysis for the European Commission and market research organisations, as well as research and consultancy for NGOs and the National Union of Students (NUS) in equality and diversity issues. In addition, Louisa has been involved in the student and feminist movement for years both in France and the UK.
Jenny started her PhD at the Gender Institute in 2015. Her ESRC-funded project will analyse panel and birth cohort data to investigate gender and class differences in career paths and how these have changed over time in the UK. Her research interests include parental employment and the combination of paid work and caring responsibilities.
Jenny completed her MSc in Social Policy (Research) at the LSE with distinction in 2008. Prior to returning to the LSE to start her PhD she worked on as a quantitative data analyst at NatCen Social Research.
Alaa started her LSE-funded PhD at the Gender Institute in 2016, examining sex and domestic worker mobilization in 20th century Egypt at the margins of the labour movements. Her work focuses on the role of class, race, and gender in shaping the securitization of women's sexuality and the value of reproductive labour. Her research interests include: Middle East studies, feminist historical materialism, decolonial and post-colonial studies, labour and social movement theory.
Before joining the GI, Alaa was awarded her MSc in Labour, Social Movements and Development from the Development Studies department at SOAS in 2015 with distinction. She also holds a BA in Political Science from the American University in Cairo. In addition, Alaa has a long history working with various NGOs in Cairo and is fluent in Arabic and English.
Ilana started her LSE funded doctorate at the Gender Institute in 2014, and is currently an associate researcher to the research program GEDI (Genre et discriminations sexistes et homophobes), coordinated by the University of Angers. She has contributed to the Dictionnaire des féministes to be shortly published by the University Press of France (PUF).
Her doctoral thesis examines the socio-genesis of lesbian collective identities in France in the 1970s and 1980s and their relation to feminist social movements, through the lenses of political, cultural and theoretical circulations between France and the United States. She pays particular attention to the transatlantic controversies revolving around the definition of the political subject of feminism and to the epistemological dissonances between feminist and lesbian subject-positions.
Ilana's broader research interests include social movements, socio-history of feminist and LGBT movements, lesbian studies, the practices of oral history, epistemology of history, feminist materialism and queer theories.
She holds a BSc and an MA from Sciences Po Paris, an MSc in Gender Studies with Distinction from the University Paris 8, and a BA and MSc in Art History from Paris 1 – La Sorbonne. In 2011, she co-curated with Jonathan D. Katz and Julia Haas an exhibition at the Leslie/Lohman Museum of Gay and Lesbian Art on 1970s lesbian-feminist photography in the United States.
Miha studied Sinology and Philosophy at the University of Ljubljana, followed by an MA course in Gender Studies at SOAS. He joined the LSE Gender Institute in 2013 to further pursue his research interest around anti-authoritarian thought. In his PhD project, Miha is exploring Chinese anarchist politics of intimacy through a conversation with cognate social and political theories - mainly contemporary anarchist, feminist and queer approaches. So, besides investigating specificities of various Chinese anarchist critiques of marriage and the family, Miha is also thinking about the potential intellectual contribution of Chinese anarchist thought to the contemporary debates on the politics of intimacy.
E-mail: email@example.com
Jacqui joined the Gender Institute in 2014. Her project explores more recent conceptualisations of vulnerability within feminist theory, by considering the framing of vulnerability within current UK policy discourses. Jacqui's research interests include queer and feminist theories on affect and emotion, narrative, discourse, and temporality.
Prior to joining the Gender Institute, Jacqui completed an MA with distinction in Gender, Media and Culture at Goldsmiths University, London, and a Bachelor of Arts (hons) in Politics and Sociology at the Australian National University, Canberra. Jacqui has previously worked as a policy researcher for a community advocacy organisation.
Julia graduated summa cum laude from the University of Ottawa in 2012 with a Bachelors of Social Sciences degree in International Studies and Modern Languages (French Immersion). She completed her Masters of Arts in Global Development Studies in 2014 at Queen's University, Canada, where she was funded by both the Social Sciences and Humanities Research Council of Canada and the Ontario Graduate Scholarship. She is fluent in French and Spanish.
Julia's doctoral project builds on her previous research and work experience in Guatemala, and explores the materiality of femicide and other forms of violences against women in Guatemala's Northern Transversal Strip. Her research interests include critical feminist political economy, feminist international relations, violences against women, feminist historical materialism, extractivism, and masculinities. She holds a Doctoral Fellowship from the Social Sciences and Humanities Research Council of Canada and a PhD Studentship from the LSE. Julia is also a Visiting Researcher at the Women's Institute of the University of San Carlos in Guatemala City.
Aiko joined the Gender Institute in 2015. Her LSE-funded research focuses on gender training for uniformed personnel (military and police) engaged in international interventions. Her doctoral thesis examines gender training materials and practice with a view to identifying how gender knowledge is translated and deployed in military and police institutions, and how such training might help 'do' gender and security differently. Aiko's broader research interests include questions linked to the international 'Women, Peace and Security' -agenda and its implementation, feminist security studies, critical military studies, and the politics of international military interventions and peacebuilding.
Aiko previously worked on questions related to gender and security at the Geneva Centre for the Democratic Control of Armed Forces (DCAF) and the European Commission's Directorate-General for Home Affairs. Her professional experience includes policy research and technical advice and capacity-building in the field of gender and security sector reform. She holds an MA in Political Science from the Graduate Institute of International and Development Studies in Geneva and an MA (undergraduate) with First Class Honours in International Relations from the University of St Andrews. She is fluent in English, Finnish and French.
Billy Holzberg started his PhD at the Gender Institute in 2015 in which he examines what role emotions play in the framing of and public reaction to the 'refugee crisis' in Germany. He is interested in theories of affect, queer studies, postcolonial epistemologies and critiques of political economy. He has been awarded an LSE studentship for his doctoral project and is associated with the International Inequalities Institute as a participant of their Leverhulme scholars programme.
Billy holds a Bachelor in Liberal Arts from the Amsterdam University College and an MSc in Culture and Society from LSE's sociology department where he received the Hobhouse Memorial Prize for the best MSc performance and dissertation in sociology in 2014. Billy works as a freelancer for cultural consultancies and has been engaged with a number of queer, feminist and postcolonial research and activist groups. He is a member of NYLON and an alumnus of the German National Merit Foundation.
Email: email@example.com
Aura started her ESRC-funded doctoral research at the Gender Institute in 2014, exploring the role of sexuality and sexual regulation within recent welfare and immigration policy in the UK. Her research interests include citizenship and state building, inequalities and social justice, theories of affect and the psyche, questions of epistemology, and queer theory.
Aura completed her MSc in Gender with distinction at the GI in 2011, and has a BA in Politics and Chinese from the School of Oriental and African Studies (SOAS). She has a long history of working with refugees and people in immigration detention, and her professional experience also includes training and advice for campaigners and activists.
Magdalena joined the Gender Institute as a PhD student in September 2013. She holds a BA in Study of Religions and Hispanic Studies and an MA in Contemporary Religions from University College Cork, Ireland.
Her LSE funded research looks at the phenomenon of religiously motivated reparative therapy (sexual orientation conversion therapy) in contemporary Poland. In this project she examines the ways in which negotiations around sexuality come to bear on postsocialist modernity, paying particular attention to questions of class and the effects of socio-political transformation that took place in Poland post 1989, and using reparative therapy as a site from which the complexity and ambivalence of such negotiations can be engaged with.
Magdalena's research interests include – but are not limited to – sexuality, modernity, postsocialism, religion, LGBTQI activism, class, Central and Eastern Europe, globalization, social change, and transnational movements.
Swati is at LSE's Gender Institute as a visiting research student in 2017 on a Commonwealth Scholarship. She is a PhD research scholar at the Tata Institute of Social Sciences (TISS) since 2014. Her doctorate focuses on 'South Asia's Human Development Puzzle' across Bangladesh, Nepal, Sri Lanka and India.
She has an MSc in Development Studies from the School of Oriental and African Studies (SOAS) in 2003 and an MA in Management from TISS in 2000. Prior to starting her PhD she worked for a decade on policy research with several civil society organisations including Oxfam in India. She is also a social activist on the right to food and education.
Email: firstname.lastname@example.com
Priya started her LSE funded doctorate that the Gender Institute in 2016. Her work evaluates discourses around sexual violence in India, and explores possibilities for agency and resistance within gendered regimes of sexual violence.
Prior to joining the GI, Priya worked with feminist NGO Nirantar and New Delhi in its Gender and Sexuality programme. Priya also spend three years with the Economic Development Board of Singapore, working on developing and implementing policy in the natural resource sector.
Priya has a Masters in Development Studies from the Institute of Development Studies, Sussex; and a BSc in Information Systems Management with a second major in Political Science from the Singapore Management University.
Amanda is a first year PhD student. Her research explores feminist development alternatives, agrarian change, ecology, and inequalities in Hawai'i. She completed her MSc in Gender, Development and Globalization at the GI in 2007 and has worked in government and women's rights issues in the US, UK and Argentina. She continues to offer consulting support to research and advocacy organizations working on issues of gender, environment and social change. Her research interests include feminist development alternatives, feminist economics, social movements, queer theory, theories of affect and art practice in social science research.
Lindsay's research explores the lives of British orthodox Jewish women (BOJW). She is interested in the marked ways in which the intersection of these identities troubles notions of agency. Lindsay argues that theories of agency concerned with the religious subject must be grounded in real women's lives; especially those who challenge and shift the notion of the BOJW through their day to day experiences as religious subjects within British society. Her work attempts to challenge as well as employ contemporary theorists, in particular Judith Butler and Saba Mahmood, in their framing of agency of the religious subject. She is particularly interested in Butler's theory of 'Cultural Intelligibility' as it relates to the performance of religious life. She navigates through the pertinent theorists by using interviews with BOJW and exploring contemporary practices within the British orthodox communities. Moving from a binary sense of (only) the mis-act as agentic; through the 'inhabiting norms...as a modality of action', Lindsay attempts to broaden the meaning of agency – one which evokes the sense that acts reflect religious norms back on to the religious community, such that agentic subjects continually shift 'traditional' behavioural norms, and in turn, what might be considered intelligible.
Lindsay's received her BSc in Speech and Language Pathology from the Central School of Speech and Drama, London, before studying in Jerusalem, Israel for five years in institutions which promoted post-graduate Jewish Studies for women (Nishmat and Midreshet Lindenbaum); subjects included: Talmud, Jewish Law, Biblical Narrative Analysis and Jewish Philosophy. On her return to the UK, she graduated as a Susi Bradfield Scholar from the London School of Jewish Studies (LSJS) and received her MSc in Gender Studies from the LSE's Gender Institute in 2009.
In 1998, Lindsay became a faculty member of the LSJS where she has lectured, written and convened courses for over 15 years, focussing on women in Biblical narrative and women in Jewish Law and the Talmud. She lectures at Kings' College London, for the United Synagogue and at Jewish communities throughout the UK. She speaks at national and international conferences on Judaism and Gender, writes regularly for the Jewish Chronicle and is involved in several UK projects promoting orthodox Jewish women's ritual participation and leadership. She has appeared on the BBC's Woman's Hour, Beyond Belief and the world service. Lindsay is also involved in several inter-faith projects and is a member of the Cambridge Co-Exist Leadership Programme.
Emma has a BA (hons) in French and Politics from The University of Sheffield, an International Diploma in Politics from Sciences-Po (Paris), and an MSc in Gender (Research) from the Gender Institute at LSE. She has taught Undergraduate and Masters courses at the Université de Versailles Saint-Quentin-en-Yvelines (France) and Undergraduate and Masters courses at LSE (in the Department of Sociology and the Gender Institute, respectively).
Emma's ESRC-funded PhD explores the appeal and effects of gay progress narratives. The project seeks to identify and analyse new discursive and material inclusions and exclusions, arguing that these borders have been reconfigured through the changing position of homosexuality in stories of progress that are told about the world, the nation, the city and the neighbourhood. Previously, Emma worked on LGBTQ asylum and the constrained sexual stories that can be told through asylum applications.
Hannah started her ESRC-funded PhD at the Gender Institute in 2016. Her thesis focuses on understanding the relationship between gendered organisational cultures and discourses in foreign policy-making institutions and approaches to international peace and security. Hannah also works as a Researcher at the LSE's Centre for Women, Peace and Security. Previously, Hannah worked as a policy adviser on gender, peace and security issues for Saferworld, an international peacebuilding NGO, where she conducted research and analysis on gender and conflict in the Middle East, North Africa, South and Central Asia, as well as doing advocacy toward national and international policymakers. She has also worked as a researcher in the UK Parliament with a focus on foreign policy issues, and prior to that worked with a women's rights organisation in the Occupied Palestinian Territories.
Hannah holds a BA in Philosophy, Politics and Economics from the University of Oxford and an MSc in Gender and International Relations from the University of Bristol. Email: firstname.lastname@example.com
Gender Institute PhD Students:
Acciari, Louisa
Chanfreau, Jenny
El-Mahrakawy, Alaa
Eloit, Ilana
Fugina, Miha
Gibbs, Jacqui
Hartviksen, Julia
Holvikivi, Aiko
Holzberg, Billy
Lehtonen, Aura
Mikulak, Magdalena
Narayan, Swati
Raghavan, Priya
Shaw, Amanda
Simmonds, Lindsay
Spruce, Emma
Wright, Hannah
Use of this website is subject to, and implies acceptance of, its Terms of use (including Copyright and intellectual property, Privacy and data protection and Accessibility). The London School of Economics and Political Science is a School of the University of London. It is a charity and is incorporated in England as a company limited by guarantee under the Companies Acts (Reg no. 70527).The registered office address of the School is: The London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK; Tel: +44 (0)20 7405 7686

subset: commoncrawl


text:
Posted by anonymous
Ms Martin was very patient and understanding. She explained all my options and thoroughly answered all my questions. She was often immediately available to take my calls, but replied quickly if I had to leave a message. I was very satisfied with her services and would strongly recommend her to others.


text: Great home on a popular Point Breeze block! This renovated home has a large kitchen with granite counters, stainless steel appliances and a tile backsplash. There is a beautiful brick facade and lots of natural light throughout. Other amenities include 3 bedrooms, hardwood floors, central air, large rear patio and tons of storage. Walk everywhere in Point Breeze and Graduate Hospital. Close to Broad Street and the Business District. Great buy!! Move right in!


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Contact Us
The Recorder
When trial commenced earlier this month in U.S. District Judge William Alsup's courtroom, Oracle Corp. seemed to have all the momentum in its copyright rematch with Google Inc.
It had an energetic new trial team led by Peter Bicks and Annette Hurst from Orrick, Herrington & Sutcliffe. It had a streamlined case. And it had a favorable determination from the U.S. Court of Appeals for the Federal Circuit establishing that Google infringed copyrights for basic elements of the Java programming language in building its hugely profitable Android mobile operating system. What the jury was left to decide was whether Google's use of 37 application programming interfaces, or APIs, in Android was a protected fair use under copyright law.
But on Thursday, after two weeks of trial and three days of jury deliberation, a San Francisco federal jury of eight women and two men sided with Google and said "yes" on that single question. The verdict stopped the case short of a damages phase where Oracle was seeking nearly $9 billion.
Google won over the jury by largely sticking to its guns from the previous trial four years ago. The search giant brought back the same legal team, led by Robert Van Nest of Keker & Van Nest. He and his colleagues repeated a familiar narrative for anyone who followed along back in 2012. Oracle's predecessor, Sun Microsystems, which developed Java, initially welcomed Android with open arms, they said. Oracle only sued, Google's lawyers complained, after the company's own efforts to develop a Java-based smartphone were fruitless. The APIs themselves, Van Nest said in closing arguments, were "a system and a method of organization," not a creative work due a higher degree of copyright protection.
Copyright expert Peter Menell, a professor at UC-Berkeley School of Law, said that Google's lawyers likely persuaded jurors about the level of copyright protection that APIs are due. "Declaring code is not poetry," he said. Menell said he expects the jury's verdict to remain intact in the face of posttrial motions and a potential appeal. "I just think it is going to be very surprising to have this completely reversed in any sense," Menell said.
But Oracle has vowed to fight on, with GC Dorian Daley issuing a statement shortly after the verdict was handed down Thursday afternoon saying the company would appeal.
Ira Levy of Goodwin Procter said that "the battle is far from over." Levy, who isn't involved in the case, said that Alsup's jury instructions, which didn't strictly follow the guidance the Federal Circuit gave the judge on fair use, would be a likely target on appeal. (See "Handicapping the Googacle Appeal.")
But should the verdict stand, Levy thinks it provides a road map for winning similar code copyright cases by "diminishing the value of the APIs as being something new and creative." The ultimate outcome, Levy said, could decrease parties' willingness to take a license to copyrighted APIs and make parties who think they have infringement claims less likely to sue.
While the litigation battle has been between the two Silicon Valley giants, jurors saw the conflict play out through the back-and-forth between the legal teams. Orrick's Bicks, who replaced Morrison & Foerster partner Michael Jacobs as Oracle's lead lawyer, took an energetic and, at times, confrontational approach. After coming across as low key in pretrial proceedings, Bicks came out hot during opening statements and developed a mellifluous moniker for Google's defense, calling it the "fair-use excuse." The 56-year-old New York litigator repeatedly returned to internal Google emails that said alternatives to Oracle's Java code "all suck" and that Google's own equivalent was "half-ass" at best.
He and Hurst often wielded those emails during cross-examinations to try to discredit Google's witnesses, particularly Android founder Andy Rubin, who had written that certain Java APIs were "copyrighted" in another email that came up at trial. Hurst also prodded Rubin on Google's deal to acquire Android, trying to show that Rubin was motivated to copy the APIs to receive incentive payments for getting the operating system onto phones quickly.
But after this second trial, Oracle once again comes out of Alsup's courtroom with empty hands. After the first trial, members of Oracle's legal team could console themselves with the jury's decision that Google had in fact infringed Oracle's copyrights—they'd just run into Alsup ruling against them on copyrightability. Now, however, Oracle's side is left with nothing but a jury loss.
"Relative to where they were before," said UC-Berkeley's Menell, "they're far worse off."
(415) 391-5400
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12/15/2016 Bob Van Nest cements himself as Silicon Valley's copyright defense lawyer.
12/05/2016 Bob Van Nest was selected as one of the year's best litigators.
06/03/2016 With $9 billion on the line, Google Inc. never lost faith in its lawyers at Keker & Van Nest. That decision paid off late last week after a second trial in the case, when a jury sided with the online search giant.
09/24/2015 This is Judge Alsup's second time hearing the Oracle-Google case, after overturning the jury's verdict and determining that Oracle's Java programming interfaces could not be copyrighted.
05/23/2012 Keker & Van Nest bested Oracle's legal team, who were unable to secure any significant wins during the multiphase five-week trial.
05/07/2012 Partial verdict in Oracle-Google case seen as setback for Oracle.


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I'm big into roller sports. roller derby, roller hockey and even skated with the world famous LA T-Birds for a while.
I also garden a lot. You have never truly tasted fruits and vegetables until have had them right off the vine.
Nobody wants to be lonely, but girls spend so much time looking for perfection they let great people slip away.


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PVR to release Ashoka-The Hero on 7 January
MUMBAI: Animation house Illusion Interactive's Ashoka –The Hero will be released on 7 January by PVR Pictures' Springboard Films.
Made on a budget of Rs 25 million, the 2D film will released with 50 prints.
Ashoka - The Hero is the first feature to come out from the studio's kitty.
Ashoka –The Hero is the story of a young boy Ashoka who wants to grow up and help others. His inspiration is his father, a policeman who died in the line of duty. The boy finds a powerful medallion, created by Emperor Asoka after the war of Kalinga, to protect mankind from self destruction and evil.
After getting these powers, Ashoka becomes a super hero and learns to use his powers and help others. How he fights off the corruption of power and saves the city forms the crux of the film.
Illusion Interactive is an independent animation studio based in Mumbai with its strengths in concept development and production.


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Frank Archibald MacDougall
Frank MacDougall (16 June 1896 - 27 June 1975) was a pioneering forest ranger in Ontario, Canada. Known as the "flying Superintendent of Algonquin Park", he was important in the development of the park system in the province and for the use of airplanes in forestry.[1]
Life and career[edit]
Of Loyalist descent, Frank MacDougall was born on 16 June 1896 in Toronto, Ontario, Canada, and died 27 June 1975 in Toronto. He was raised in Carleton Place, Ontario, where he was active in sports, becoming an expert canoeist as a member of the Carleton Place Canadian championship war canoe team for 1/2 mile in 1913 and 1/2 and one mile in 1914.
After a year in the 42nd regiment as a student, he enlisted in the Canadian Expeditionary Force on 17 September 1915 and arrived in England on 14 February 1916. He fought in the Battle of Vimy Ridge in the 3rd Battalion of the 1st Canadian Division. On 6 September 1917, he was admitted to hospital suffering from the effects of a gas attack, returning to duty on the 16th in time to join the Battle of Passchendaele. He returned to Canada and was demobilized on 16 June 1919.[2] On medical advice due to the gassing, he decided to pursue an outdoor career, and entered Forestry at the University of Toronto.
While working in the James Bay survey in the summer of 1922, he observed the Great Fire of 1922 around Haileybury.
Upon graduation in 1923 (B.Sc.F.), he immediately entered the Ontario Department of Lands and Forests and was assigned as Assistant District Forester in Algonquin District, which includes the Algonquin Provincial Park, Ontario.
It was in the Department that MacDougall saw the value of aircraft for forest protection and patrol and took the opportunity of becoming a pilot, eventually achieving an instrument rating and the equivalent of a commercial pilot's license. He later moved to Sault Ste. Marie as Forester Inspector and then in 1926 was appointed District Forester. In 1931 he was assigned as Superintendent of Algonquin Park, and District Forester of the Algonquin area. From his first days in Algonquin Park he was provided with his own plane, a Fairchild KR-34 open cockpit biplane, together with a mechanic and maintenance personnel. That airplane is now in the Canadian Bushplane Heritage Centre.[3]
The open airplane was used for patrol purposes on floats in the summer and skis in the winter. For the latter MacDougall had fur lined pants up to his armpits, fur lined boots, fur lined helmet, fur trimmed goggles and his mitts were also fur lined up to his elbows. He would return from a winter trip in this gear shivering with cold but the poaching trade took a sharp decline. Around 1939 he finally acquired a closed cabin airplane, the Stinson Reliant SR-10, and this served for many years until, during a routine maintenance, serious corrosion problems were discovered and the plane had to be retired.
MacDougall was an accomplished amateur musician, who also made violins as a hobby. He added a woodworking corner to his Park office where he made violins in his spare time. He used his knowledge of woods to good effect and scoured the country looking for scraps of old, fine grained woods which he then traded with professional violin makers for tools and advice. He made over 6 violins which were presented to friends, several of whom were professional players, who appreciated his quality of sound. One is still in the family.
In 1941 MacDougall was promoted to the highest non-elected position in the Civil Service when he became Deputy Minister of Lands and Forests, stationed in Toronto. It was in that position that he assisted with the writing of a design proposal for a bush plane using his own experiences and that of the Provincial Air Service pilots for the specification. The department promised orders for 20 planes as an incentive. DeHavilland aircraft of Canada secured the contract for the Beaver aircraft which became the world standard in performance for bush planes .
MacDougall's department was one of the earliest to develop the use of airplanes for fire detection and the water bombing of forest fires.[1] For his work in forest protection and the development of the Beaver he was awarded the McKee Trophy, Canada's highest aviation award.[3]
MacDougall had the use of the first production Beaver and then subsequent Beavers headquartered during the summers in Toronto and flew them during inspection trips from Toronto until his retirement in 1966.
MacDougall was first married to Pearl Nugent (1885–1946) from whom he had three children, two of whom survived into adulthood and second married to Merren Murray (-1983) from whom he had a daughter.
Lists of honors and awards[edit]
- Carleton Place Canoe Club; war canoe champions 1/2 mile, 1913; 1/2 and 1 mile, 1914
- British War Medal and Victory Medal [2]
- Awarded the McKee Trans-Canada Trophy in 1964[1]
- Companion of the Order of Flight, Alberta, 1973
- Inducted as a Member into Canada's Aviation Hall of Fame 31 December 1973
- Named to the Brotherhood of the Silver Wings of the Northwest Territories, 1974
- Highway 60 in Algonquin Park, between the east and west gates, designated as The Frank MacDougall Parkway, August 6, 1976
After his death a memorial fellowship was established at the University of Toronto, the Frank A. MacDougall Fellowship; value up to approximately C$2,195 annually.
- ^ a b c Sutherland, Alice Gibson. Canada's Aviation Pioneers: 50 Years of McKee Trophy Winners. McGraw-Hill Ryerson. ISBN 0-07-082704-4.
- ^ a b war record of Frank Archibald MacDougall, service number 304619, National Archives of Canada
- ^ a b "The Flying Superintendent's Fairchild". The Country Connection, Winter/Spring 1999.


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Well, it looks like Apple is experiencing some difficulty getting the iWatch up and running. According to Jessica Lessin of The Information, Apple is currently experiencing a number of iWatch problems pertaining to battery life along with the screen technology itself. Specifically, Lessin relays that Apple this past year "halted advanced prototyping of some unknown pieces with one manufacturer late last year."
Qualifying that statement, Lessin notes, as did Tim Cook during an earnings conference call some time ago, that news emanating from a lone manufacturer in and of itself may not be a valid data point.
Notably, the report jibes with a previous report we saw earlier this week from Digitimes, which claimed that early production on iWatch prototypes have seen rather low yields on account of issues resulting from surface treatments on the device.
Several wearable devices such as Apple's iWatch and Qualcomm's Toq are reportedly seeing less than 50% yield rates due to difficulties applying surface treatments on their metal injection molded (MIM) chassis, according to sources from the upstream supply chain.
All told, it's hard to know what to make of these rumors. After all, any new product goes through technical hurdles and challenges before making it to market. The iPhone is a prime example. In Frank Vogelstein's recent book about the Apple/Google rivalry, he recounts how the iPhone was very much a beta product even when Steve Jobs went up and introduced it on stage. It would frequently crash and also experienced connectivity issues, but Apple obviously worked out all of those kinks in time for its June 2007 launch.
Lastly, Lessin relays that Apple has a "sizeable team" working on the project. Recall that Bloomberg many months ago indicated that Apple had about 100 folks working on the rumored device.
All that being said, it's probably well advised to be patient and see what Apple has in store for us in 2014.
On a related note, The Information also adds that former Apple engineer Bryan James, who was originally part of the iWatch team, has since left Apple to work for Nest.
via Business Insider


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