EP0509049A1 - Procede de prediction de risque atherosclereux - Google Patents

Procede de prediction de risque atherosclereux

Info

Publication number
EP0509049A1
EP0509049A1 EP91902894A EP91902894A EP0509049A1 EP 0509049 A1 EP0509049 A1 EP 0509049A1 EP 91902894 A EP91902894 A EP 91902894A EP 91902894 A EP91902894 A EP 91902894A EP 0509049 A1 EP0509049 A1 EP 0509049A1
Authority
EP
European Patent Office
Prior art keywords
hdl
resonance
ldl
plasma
vldl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91902894A
Other languages
German (de)
English (en)
Other versions
EP0509049A4 (fr
Inventor
Eric T. Fossel
Jan Mcdonagh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beth Israel Deaconess Medical Center Inc
Original Assignee
Beth Israel Hospital Association
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beth Israel Hospital Association filed Critical Beth Israel Hospital Association
Publication of EP0509049A4 publication Critical patent/EP0509049A4/fr
Publication of EP0509049A1 publication Critical patent/EP0509049A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/465—NMR spectroscopy applied to biological material, e.g. in vitro testing
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment

Definitions

  • the present invention relates to a method for predicting atherosclerotic risk in a living patient.
  • the plasma lipoproteins are complexes in which the lipids and proteins occur in a relatively fixed ratio. They carry water-insoluble lipids, such as cholesterol and cholesterol esters for eventual cellular utilization between various organs via the blood, in a form with a relatively small and constant particle diameter and weight. While all cells require cholesterol for growth, excess accumulation of cholesterol by cells is known to result in a disease state referred to as atherosclerosis. It is also known that total serum cholesterol can be correlated with the incidence of atherosclerosis.
  • Human plasma lipoproteins occur in four major classes that differ in density as well as particle size as shown in the table below.
  • the characteristic flotation rates in Svedberg flotation units (S f ) of the lipoproteins are determined in an NaCl medium of density 1.063 g ml - 1 at 26°C, in which lipoproteins float upward and simple proteins sediment.
  • the plasma lipoproteins contain varying proportions of protein and different types of lipid.
  • the very low-density lipoproteins contain four different types of polypeptide chains having distinctive amino acid sequences.
  • the high-density lipoproteins have two different types of polypeptide chains, of molecular weight 17,500 and 28,000.
  • the polypeptide chains of the plasma lipoproteins are believed to be arranged on the surface of the molecules, thus conferring hydrophilic properties.
  • the very low-density lipoproteins and chylomicrons there is insufficient protein to cover the surface; presumably the polar heads of the phospholipid components also contribute hydrophilic groups on the surface, with the nonpolar triacylglycerols in the interior. Biochemistry, Lehninger, Worth Publishers, Inc., New York, 1975, p.301.
  • the different lipoprotein classes contain varying amounts of cholesterol.
  • a total serum cholesterol measurement is an average of the amount that each lipoprotein class contributes to the total serum lipoprotein.
  • the present invention is a method for predicting atherosclerotic risk in a living patient.
  • a sample of a patient's bodily fluid is subj ected to proton nuclear magnetic spectroscopy to generate a water-suppressed proton nuclear magnetic resonance spectrum.
  • a curve resolution procedure is performed on the methyl or methylene resonance envelope to allow classifying of the resonances as resulting from very low density lipoproteins, low density lipoproteins, high density lipoproteins and chylomicrons.
  • the amplitude of the high density lipoprotein resonance is measured and a mean normalized value calculated.
  • the measured amplitude is then classified into a normal or abnormal category compared to a predetermined standard for which an abnormal spectrum indicates a high atherosclerotic risk.
  • VLDL, LDL, HDL and chylomicron-cholesterol values are obtained using standard purified lipoprotein preparations. Standard curves are prepared in which peak height is plotted versus concentration for the methyl or methylene resonance as well as peak area versus concentration for the methyl or methylene resonance. Test sample results are then compared to the standard curves to obtain the lipoprotein concentrations in the test sample. The triglyceride level is determined by adding the peak areas of the chylomicron and VLDL components. A risk index is determined using the peak heights and peak areas of the resolved components.
  • an object of the present invention is to provide a method for predicting atherosclerotic risk in a living patient.
  • Another object of the present invention is to provide the concentrations, expressed in mg/dl, of the VLDL, LDL and HDL components as well as the chylomicron and triglyceride levels.
  • FIG. 1 is a typical 360 MHz NMR spectrum of the non-water components (water suppressed) of a plasma sample from a healthy control obtained in accordance with the present invention
  • FIG. 2 is an NMR spectrum for the same plasma sample from which the spectrum of Fig. 1 was obtained, using the same equipment and pulse frequency, except without water suppression;
  • FIG. 3 is an expanded view of the methyl and methylene region of the Fig. 1 sample
  • FIG. 4 is an NMR spectrum of the methyl and methylene regions of a plasma sample of a patient with a high atherosclerotic risk
  • FIG. 5 schematically illustrates the apparatus used to perform the method of the present invention
  • FIG. 6 shows the results of a study performed using the method of the present invention
  • FIG. 7 shows an NMR spectrum of the methylene region and the four lipoprotein components as obtained using the curve resolution procedure.
  • the present invention is a method for predicting atherosclerotic risk in a living patient.
  • the test for high atherosclerotic risk which is an object of the present invention, will typically be performed in vitro.
  • the process operates on any lipid-containing body fluid, blood, or bone marrow plasma. Whole blood, serum, or plasma may be used. While the test may be performed on any such lipid-containing body fluid, work to date has focused on blood plasma and thus in a preferred embodiment of the present invention plasma is used.
  • the test sample need not be fasting.
  • a sample of patient's whole blood or plasma is subjected to proton nuclear magnetic resonance spectroscopy to generate a nuclear magnetic resonance spectrum. Since components of the NMR spectrum which have significant predictive value may be masked by other materials, such as the water signal, steps are taken to eliminate the masking, thereby producing an informative NMR spectrum.
  • FIG. 7 shows a methylene resonance NMR spectrum 1 before the curve resolution procedure and the spectrum as resolved into the four components; chylomicrons 2, VLDL 3, LDL 4 and HDL 5.
  • the amplitude of the high density lipoprotein resonance, the amplitude of the low density lipoprotein resonance and the amplitude of the very low density lipoprotein are then measured and a mean normalized value calculated for each.
  • the measured amplitudes are then classified into a normal or an abnormal category compared to a predetermined standard for which an abnormal spectrum indicates a high atherosclerotic risk, i.e., high HDL is a sign of low risk, high LDL is a sign of high risk.
  • a water-suppressed proton NMR spectrum of a preprandial or postprandial plasma sample (or serum sample) is obtained and the chemical shift values of VLDL, LDL, HDL and chylomicrons in the methyl or methylene resonance are identified using a curve resolution program.
  • the area, line-width, and height of the VLDL, LDL, HDL and chylomicron components are then determined.
  • the heights of the peaks are measured with a ruler or computer from the center of the baseline noise to the top of the peak.
  • an LDL-cholesterol value is obtained using a standard purified LDL preparation.
  • Standard curves are prepared in which peak height is plotted versus concentration for the methyl or methylene resonance as well as peak area versus concentration for the methyl or methylene resonance.
  • Test sample results are then compared to the standard curves to obtain the LDL-cholesterol concentration in the test sample.
  • HDL-cholesterol value is then obtained using a standard purified HDL preparation.
  • Standard curves are prepared in which peak height is plotted versus concentration for the methyl or methylene resonance as well as peak area versus concentration for the methyl or methylene resonance.
  • Test sample results are then compared to the standard curves to obtain the HDL-cholesterol concentration in the test sample.
  • VLDL-cholesterol value is then obtained using a standard purified HDL preparation.
  • Standard curves are prepared in which peak height is plotted versus concentration for the methyl or methylene resonance as well as peak area versus concentration for the methyl or methylene resonance.
  • Test sample results are then compared to the standard curves to obtain the VLDL-cholesterol concentration in the test sample.
  • a risk index is then determined using the resolved components of either the methyl or methylene resonance using one of the following equations:
  • values for the risk index of 3.9 + 4.5 at a proton frequency of 360 MHz (8.45T) or 400 MHz (9.40T) indicates a normal atherosclerotic risk or a healthy/normal individual, and a value of 11.0 ⁇ 4.1 indicates a high atherosclerotic risk.
  • the concentration of VLDL, LDL, HDL chylomicrons in mg/dl is determined. Values for each lipoprotein are obtained using a standard purified lipoprotein preparation. Standard curves are prepared in which the known lipoprotein concentration is plotted against peak area for each lipoprotein fraction using either the methyl or methylene resonance. Test sample results are then compared to the standard curves to determine the concentration in mg/dl of each lipoprotein fraction; VLDL, LDL, HDL and chylomicrons. The triglyceride concentration is then determined by adding the peak area of the chylomicron component to the peak area of the VLDL component. The peak area is measured by a standard mathematical method using a computer program to carry out the calculations.
  • FIG. 1 shows water suppressed proton spectrum of a healthy control
  • FIG. 2 shows a proton spectrum of the same sample without water suppression.
  • the truncated resonance line of water is denoted A in FIG. 2.
  • the resonance lines between 2 and 3 ppm (part per million of resonance frequency) arise from the methyl and methylene groups of the lipoprotein lipids.
  • An expanded view of this region of the proton spectrum is shown in FIG. 3 for a normal control.
  • FIG. 4 shows an NMR spectrum of the methyl and methylene regions of a plasma sample for a patient with a high atherosclerotic risk.
  • proton NMR spectroscopy is performed on a human blood plasma sample with the water signal is suppressed.
  • the water suppressed proton NMR spectrum obtained is dominated by resonances of plasma lipoprotein lipids. Without water suppression, these non-water resonances are virtually overwhelmed by the water. Signal averaging allows observation of resonances associated with non-water body fluid components, at high magnetic fields, even in the presence of water resonance.
  • modern NMR spectrometers can almost completely suppress the water proton resonance.
  • the water suppressed proton NMR spectrum of plasma is essentially plasma lipoproteins and a few low molecular weight molecules .
  • the plasma protein protons are obscured because they comprise a broad smear of unresolved resonances. The sharper resonances of the more mobile lipoprotein protons are superimposed on this broad background.
  • the present invention uses one of a number of conventional water suppression techniques, i.e., techniques for suppression of the water proton NMR signal.
  • conventional water suppression techniques i.e., techniques for suppression of the water proton NMR signal.
  • Numerous techniques have been devised to suppress the water proton NMR signal in other contexts. These may be broadly divided into two categories: (1) those that attempt avoiding excitement of the water proton signal, e.g., rapid scan correlation spectroscopy and the selective excitation technique, and (2) those that arrange for the water proton magnetization to be extremely small at the time the observed radio frequency (rf) pulse is applied, e.g., the inversion recovery technique and saturation.
  • rf radio frequency
  • any conventional modern NMR spectrometer may be used in the practice of the present invention. In the preferred embodiments, however, an NMR spectrometer with a magnet at constant field strength is used.
  • the NMR signal is Fourier transformed and the mean normalized HDL resonance amplitude for proton resonances of methyl or methylene groups are the NMR parameters of interest.
  • FIG. 5 illustrates a nuclear magnetic resonance (NMR) spectrometer 2 which is capable of performing proton NMR spectroscopy and which is preferably, but not necessarily, of the type that suppresses the NMR signal of water.
  • the spectrometer 2 is adapted for examination of a sample 4 which is human blood plasma contained within a test tube 6.
  • the spectrometer 2 contains means 8 for selecting the HDL NMR resonance line in the NMR spectrum of the sample 4 and measuring the mean normalized amplitude of the resonance so selected.
  • the spectrometer 2 also is of conventional construction and includes, in addition to all its other structure, a means 10 for storing a value or range of values.
  • the mean normalized HDL resonance amplitude is compared with a value or range of values which represents the value or range of values to be expected from normal patients, i.e., patients who are not at a high risk of developing atherosclerosis.
  • the spectrometer 2 also includes means 12 for classifying the measured HDL resonance amplitudes as normal or abnormal, i.e., high atherosclerotic risk, based upon the stored information. This may be done by comparison, subtraction, or any other appropriate mathematical operation.
  • the selecting and measuring means 8 is pre-adjusted to measure the mean normalized HDL resonance amplitude. This may include suppressing the water signal from the NMR spectrum of the sample 4, or may alternatively be done directly where the spectrometer 2 is sensitive enough to do so.
  • Typical spectrometers that can perform the method of the present invention are the Bruker AM-360 and the Bruker AM-500. Of course, others skilled in the art will know of similar equipment to perform the method of the present invention. Correct sample preparation and execution is essential to carry out a successful measurement on plasma. Blood is collected in tubes containing 70 ul of a solution of 15% Na 2 - EDTA and is maintained at 4°C until centrifugation. Plasma is separated and stored at 4°C until NMR analysis. Plasma samples are never frozen because freezing destroys lipoprotein lipid structural integrity. Samples which show any visible sign of hemolysis are excluded.
  • the spectra are obtained at preferably 20-22°C and most preferably at 21° C.
  • a relatively broad range of proton frequencies may be employed, e.g., 60 MHz and higher, however, 360 MHz is the most preferred frequency. If cost is not a factor, 500 MHz may be the preferred frequency.
  • the samples are shimmed individually on the area of the proton free induction decay until the full width at half height of the water resonance is 4 Hz of less. Careful shimming is of course an assumed component of good NMR laboratory technique.
  • the method of the present invention was applied to a group of 17 patients undergoing traditional lipid profile analysis. Blood was collected in non-siliconized vacutainer tubes containing 70 ul of a solution of 15% Na 2 EDTA and maintained a 4°C until centrifugation. Plasma was separated and stored at 4o C until NMR analysis. Plasma samples were not frozen because freezing destroys lipoprotein lipid structural integrity. Samples which showed any visible sign of hemolysis were excluded.
  • the linewidth (FWHH) of the EDTA resonances had to be 2 Hz or less and was often between 1.0 - 1.5 Hz.
  • FWHH linewidth of the EDTA resonances
  • most H-1 probes require detuning to avoid radiation damping.
  • the probe was detuned until the 90° radio-frequency pulse became 20 msec. In the 8.45 T spectrometer, this resulted in probe detuning of about 2 MHz.
  • the sample was spun during shimming of the Z shim coils and during data acquisition.
  • Our H-1 spectra were acquired using presaturation to suppress water and an inversion-recovery sequence to null any lactate methyl protons present.
  • the presaturation pulse was 4.0 sec, with a delay of about 0.8 sec between the 180° and 90° pulse.
  • Eight FIDs were signal averaged and then Fourier transformed following multiplication by an exponential resulting in 2 Hz line-broadening. The portion of the spectrum from 0.5 to 1.6 ppm was phased so that the baseline level at the edges of the plot was the same. This resulted in defective phasing of other (non-plotted) portions of the spectra.
  • the method of the present invention was applied to a plasma sample.
  • Blood was collected in non-siliconized vacutainer tubes containing 70 ul of a solution of 15% Na 2 EDTA and maintained at 4°C until centrifugation. Plasma was separated and stored at 4o C until NMR analysis. Plasma samples were not frozen because freezing destroys lipoprotein lipid structural integrity. Samples which showed any visible sign of hemolysis were excluded.
  • an LDL-cholesterol value was obtained using a standard purified LDL preparation.
  • Standard curves were prepared in which peak height was plotted versus concentration for the methyl and methylene resonances as well as peak area versus concentration for the methyl and methylene resonances. Test sample results were then compared to the standard curves to obtain the LDL-cholesterol concentration in the test sample.
  • HDL-cholesterol value was then obtained using a standard purified HDL preparation.
  • Standard curves were prepared in which peak height was plotted versus concentration for the methyl and methylene resonances as well as peak area versus concentration for the methyl and methylene resonances. Test sample results were then compared to the standard curves to obtain the HDL-cholesterol concentration in the test sample .
  • VLDL-cholesterol value was obtained using a standard purified HDL preparation. Standard curves were prepared in which peak height is plotted versus concentration for the methyl or methylene resonance as well as peak area versus concentration for the methyl or methylene resonance. Test sample results were then compared to the standard curves to obtain the VLDL-cholesterol concentration in the test sample.

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  • Physics & Mathematics (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Databases & Information Systems (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Pathology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Primary Health Care (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Management, Administration, Business Operations System, And Electronic Commerce (AREA)
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Abstract

Procédé de prédiction de risque athéroscléreux chez un patient vivant, utilisant la résonance magnétique nucléaire. Spécifiquement, on détermine des paramètres de RMN pour des protons de lipoprotéines de haute densité, puis on les compare à une valeur correspondante de patient en bonne santé. On emploie, lorsque cela est nécessaire, la suppression du signal de protons aqueux, afin de d'obtenir un spectre idoine pour les protons à constituant non aqueux. On identifie les individus présentant un risque athéroscléreux élevé, sur la base de l'amplitude normalisée moyenne de la résonance lipoprotéique de haute densité d'un spectre de résonance magnétique nucléaire de protons, d'un liquide biologique choisi, le plus couramment le sang total.
EP91902894A 1989-12-21 1990-12-21 Procede de prediction de risque atherosclereux Withdrawn EP0509049A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45406989A 1989-12-21 1989-12-21
US454069 1989-12-21
US63052090A 1990-12-20 1990-12-20
US630520 1996-04-10

Publications (2)

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EP0509049A4 EP0509049A4 (fr) 1992-08-27
EP0509049A1 true EP0509049A1 (fr) 1992-10-21

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EP91902894A Withdrawn EP0509049A1 (fr) 1989-12-21 1990-12-21 Procede de prediction de risque atherosclereux

Country Status (7)

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EP (1) EP0509049A1 (fr)
JP (1) JPH06505089A (fr)
AU (1) AU7142991A (fr)
BR (1) BR9007936A (fr)
CA (1) CA2071638A1 (fr)
FI (1) FI922887A0 (fr)
WO (1) WO1991010128A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021517A1 (fr) * 1992-04-10 1993-10-28 The Beth Israel Hospital Association MESURE DE PROPENSION A l'ATHEROSCLEROSE; CAPACITE D'OXYDATION DE RESIDUS D'OLEFINES DES LIPOPROTEINES ET DES LIPIDES DU PLASMA
JPH09504797A (ja) * 1993-11-08 1997-05-13 ペプチド デリバリー システムズ プロプリエタリイ リミテッド ラベルされた診断用組成物と，その使用方法
US6653140B2 (en) 1999-02-26 2003-11-25 Liposcience, Inc. Methods for providing personalized lipoprotein-based risk assessments
WO2000051054A1 (fr) * 1999-02-26 2000-08-31 Lipomed, Inc. Procedes, systemes et produits pour programmes informatiques, pour l'analyse et la presentation de resultats d'evaluation des risques bases sur la concentration mesureee par resonance magnetique nucleaire des lipoproteines dans le sang
EP1171778B1 (fr) 1999-04-22 2006-03-01 Liposcience, Inc. Methode utilisant l'irm pour determiner le risque de developper un diabete non insulino-dependant
CA2331116A1 (fr) 2001-01-15 2002-07-15 Chenomx, Inc. Identification et quantification de composes aqueux--technique et procede utilisant un systeme automatise de mesure a resonance magnetique nucleaire
CA2445431A1 (fr) * 2001-04-23 2002-10-31 Metabometrix Limited Procedes de diagnostic et de traitement de maladies des os
US20050130321A1 (en) 2001-04-23 2005-06-16 Nicholson Jeremy K. Methods for analysis of spectral data and their applications
NL1021753C2 (nl) * 2002-10-25 2004-04-27 Tno Detectie van osteoarthritis.
US9551768B2 (en) 2013-03-15 2017-01-24 East Carolina University NMR method for monitoring changes in the core of lipoprotein particles in metabolism and disease
CN105555318A (zh) * 2013-07-18 2016-05-04 香港大学 将胸膜液分类的方法
US10775458B2 (en) 2018-03-05 2020-09-15 Texas Tech University System Method and system for non-invasive measurement of metabolic health
CN110082532A (zh) * 2019-05-20 2019-08-02 吉林瑞特生物科技有限公司 脂蛋白a测定试剂盒及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0234524A2 (fr) * 1986-02-26 1987-09-02 The Beth Israel Hospital Association Procédé pour la détection du cancer utilisant la résonance magnétique nucléaire
EP0361214A1 (fr) * 1988-09-26 1990-04-04 James D. Otvos Analyse de lipoprotéines du sang par RMN

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4200588A (en) * 1973-11-16 1980-04-29 The Upjohn Company Polycycloanilines
US4940055A (en) * 1987-11-03 1990-07-10 University Of Virginia Alumni Patents Foundation High-resolution spectral signature of human arterial plaque

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0234524A2 (fr) * 1986-02-26 1987-09-02 The Beth Israel Hospital Association Procédé pour la détection du cancer utilisant la résonance magnétique nucléaire
EP0361214A1 (fr) * 1988-09-26 1990-04-04 James D. Otvos Analyse de lipoprotéines du sang par RMN

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FEBS LETTERS. vol. 219, no. 1, 13 July 1987, AMSTERDAM NL pages 239 - 243; J.D. BELL ET AL.: '1H NMR STUDIES OF HUMAN BLOOD PLASMA' *
JOURNAL OF LIQUID CHROMATOGRAPHY vol. 11, no. 3, 1 March 1988, NEW YORK, (US) pages 647 - 664; G.N. CHMURNY ET AL.: 'A COMPARISON OF HIGH PERFORMANCE GEL PERMEATION CHROMATOGRAPHY AND NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY IN THE ANALYSIS OF PLASMA FROM NORMAL SUBJECTS AND CANCER PATIENTS' *
JOURNAL OF MAGNETIC RESONANCE. vol. 59, no. 2, 1 September 1984, ORLANDO, MN US pages 268 - 274; S. COFFIN ET AL.: 'CORRELATION OF 13C AND 1H CHEMICAL SHIFTS IN BOVINE HIGH-DENSITY LIPOPROTEIN FROM TWO-DIMENSIONAL NMR' *
See also references of WO9110128A1 *

Also Published As

Publication number Publication date
AU7142991A (en) 1991-07-24
BR9007936A (pt) 1992-10-27
JPH06505089A (ja) 1994-06-09
EP0509049A4 (fr) 1992-08-27
FI922887A (fi) 1992-06-18
FI922887A0 (fi) 1992-06-18
WO1991010128A1 (fr) 1991-07-11
CA2071638A1 (fr) 1991-06-22

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