GB2360089A - Diagnostic assay for transmisible spongiform encephalopathies - Google Patents
Diagnostic assay for transmisible spongiform encephalopathies Download PDFInfo
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- G—PHYSICS
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2828—Prion diseases
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Abstract
Heart and brain fatty acid binding proteins (H-FABP, B-FABP) are markers for TSEs, especially CJD. The invention provides a diagnostic assay for either of these markers, preferably by enzyme immunoassay using a specific antibody thereto. Since H-FABP is also a marker for acute myocardial infarction (AMI), to distinguish CJD from AMI requires an assay specific to AMI, e.g. using troponin-1 or CK-MB as a marker, also to be carried out.
Description
t 2360089
"DIAGNOSTIC ASSAY FOR TRANSMISIBLE SPONGIFORM ENCEPHALOPATHIES11 BACKGROUND OF THE IN TION Field of the invention
This invention is in the field of diagnostic assay using a protein or an antibody thereto. Description of the related art
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of the central nervous system.
They can be transmitted, inherited or occur sporadically and are observed in animals, e.g. as bovine spongiform encephalopathy in cattle or scrapie in sheep, as well as in humans as Creutzfeldt-Jakob disease (CJD), Gerstman Str&ussler Scheinker syndrome, Fatal Familial Insomnia or is Kuru. They have a long incubation period, leading to ataxia, dementia, psychiatric disturbances and death. Neuropathological changes include vacuolar degeneration of brain tissue, astrogliosis and amylo:ld plaque formation. The diseases are difficult to diagnose pre- mortem.
The cerebrospinal fluid (CSF) of WD patients displays two additional polypeptide by two-dimensional polyacrylamide gel electrophoresis [Harrington, M.G. New England Journal of Medicine 315, 279 (1986), Hsich, G., Kenney, K., Gibbs, C.J., Lee, K.H. & Harrington, M. B. New England Journal of Medicine 335, 924 (1996)] The function of these 14-3-3 polypeptides rmain unclear in TSE. They can be used in a pre-mortem test for WD diagnostic evaluation, but have low specificity.
Monoclonal antibodies to the abnormal form of prion protein are available and can be used in an enzyme-lúnked immunoassay, as described in PCT Specifications WO 99/23962 and 98132710 and Schmerr, M.J., the Beckman
Coulter Pace Setter Newsletter 3 (2) 1-4 (June 1999), but these procedures have not yet been fully developed.
Development of new non-invaslve blood WD and BSE markers would help clinicians to establish early diagnosis. SUMARY OF THE INVENTION
It has now surprisingly been found that two fatty acid binding proteins (FABP), known as heart (H-FABP) and brain (B-FABP), are markers for TSEs. Thus, a TSE or the possibility thereof in a sample of body fluid taken from a patient suspected of suffering from the TSE, which comprises determining the concentration of heart or brain fatty acid binding protein (H-FABP or B- FABP) in the sample. the method is especially applicable to the is diagnosis of WD in human patients.
Conveniently the method is carried out using an antibody to H-FABP or BFABP, whereby the extent of the reaction between the antibody and the FABP in the sample is assayed and related to the concentration of FABP in the sample. The concentration thus determined is used to make or assist in making a diagnosis.
The present invention enables an assay of high sensitivity, specificity and predictive accuracy for WD to be carried out. "Sensitivity" is defined as the percentage of true positives given by the assay on samples taken from patients in whom clinical examination has confirmed WD. 11Speclficityll means the percentage of true negatives given by the assay on control samples, 1.e. from patients in whom clinical examination has not revealed WD. "Predictive accuracy" means the ratio of true positives to total positives (true + false) expressed as a percentage.
H-FABP is a known infaretion (AMI), see marker of acute Ishil, J. et al myocard.ial 1 "Serum 3 - is concentrations of myoglobin vs human heart-type cytoplasmic fatty-acid binding protein in early detection of acute myocardial infarctionll. Clinical Chemistry 1997;43 1372-1378. Therefore, in order to use an assay for H-FABP for the diagnosis of WD in humans to better advantage, it is desirable to perform another kind of assay for AMI (one in which the marker is not a FABP) in order to eliminate from the diagnosis for CiD those patients who are positive in the AMI assay.
Thus, in a particular embodiment, the invention provides a method which comprises determining the concentration of H-FABP in a first assay, as defined above, whereby a positive result indicates either a WD or acute myocardial infarction, and which further comprises carrying out a second diagnostic assay, for acute myocardial infarction (AMI) only, whereby a positive result in the H-FABP assay and a negative result in the assay for AMI indicates that the patient might be suffering from WD. Assays using Troponin-1 and Creatine Kinase-MB (CK-MB) as early biochemical markers of acute myocardial infarction (AMI) are well known and suitable for the above purpose.
A similar H-FABP and also a brain-specific fatty acid binding protein (BFABP) have been found in the brain of mice, see Pu, L. et al., Molecular and Cellular Biochemistry 198, 69-78 (1999). Brain H-FABP (not to be confused with B-FABP) is believed to differ from heart HFABP by a single amino acid substitution. However, BFABP differs considerably. Sellner, P.A. et al., it Development role of fatty acid binding proteins in mouse brain" Dev. Brain Res. 89, 33-46 (1995), estimated the DNA homology at 69%, while A. Schreiber et al., 11Recombinant human heart-type fatty acid binding protein as standard in immunochemIcal assays", Clin. Chem. Lab.
0 Med. 36(5), 283-288 (1998), mention 64% amino acid sequence homology and that a monoclonal antibody to human H-FABP is cross-reactive with human BFABP to the extent of only 1.7%.
Now that the present inventors have found that HFABP is a marker for CM, it is a very reasonable prediction that B-FABP will also be. Since B-FABP is specific to brain tissue and does not appear to react significantly with a monoclonal antibody to H-FABP, it will not give positives for AMI, making a separate assay for AMI unnecessary.
BRIEF DESCRIPTION OF THE DRAWINGS
The Figure is a graphic representation on the y-axis of H-FABP concentration represented by optical density is measurement at 405 nm, as determined by the method of the invention, for (a) a control group having neither CiD nor AMI (b) a group having AMI and (c) a group having CM.
DESCRIPTION OF PREFERRED EMBODIMENTS
For the method of assay, the sample can be taken from any convenient body fluid of the subject. The method is considered applicable to all types of TSE, including those referred to above, and to any human or animal suffering therefrom. The marker, H-FABP or BFABP, is preferably measured by an immunoassay, using a specific antibody to H- FABP and measuring the extent of the antigen (H-FABP or B-MBP) /antibody interaction. For the diagnosis of human patients, the antibody is preferably anti-human H-FABP or B-MBP. Similarly, if the patient is an animal the antibody should be to the H-FABP or B-FABP of the same animal variety, e.g. anti-bovine HFABP or B-FABP if the patient is bovine. It may be a monoclonal antibody or an engineered antibody. Conveniently a mouse anti-human, anti-bovine etc. (depending on the animal from which the sample to be is tested has been derived) monoclonal antibody is used. Antibodies to H- FABP are known, e.g. 66E2 and 67D3 described by Roos, W. et al., 11Monoclonal antibodies to human heart type fatty acid-binding protein", J. Immunol. Methods 183 149-153 (1995). Antibody 66E2 is commercially available. Also, the usual K6hler-Milstein method may be used to raise H- FABP or B-FABP antibodies. The source of protein for this purpose can be the naturally derived or recombinant DNA-prepared protein.
Recombinant human H-FABP and B-FABP have been described by Schrelber, A. supra and Shimizu, F. et al., "Isolation and expression of a cDNA for human brain fatty acid binding protein (B-FABP)11, Blochim Biophys. Acta 1354, 24-28 (1997), respectively. Less preferably, the antibody may be polyclonal.
Any known method of Immuncassay may be used. A sandwich assay is preferred. In this method, a first antibody to the FABP is bound to the solid phase such as a well of a plastics microtitre plate, and incubated with the sample and with a labelled second antibody specific to the H-FABP or B-FABP to be detected. Alternatively, an antibody capture assay could be used here, the test sample is allowed to bind to a solid phase, and the antiFABP antibody is then added and allowed to bind. After washing away unbound material, the presence or amount of antibody bound to the solid phase is determined using a labelled second antibody, anti- to the first.
In another embodiment, a competition assay could be performed between the sample and a labelled FABP or a peptide derived therefrom, these two antigens being in competition for a limited amount of anti-FABP antibody bound to a solid support. The labelled FABP or peptide could be pre-Incubated with the antibody on the solid 6 - phase, whereby the FABP in the sample displaces part of the FABP or peptide thereof bound to the antibody.
In yet another embodiment, the two antigens are allowed to compete in a single co-incubation with the antibody. After removal of unbound antigen from the support by washing, the amount of label attached to the support is determined and the amount of protein in the sample is measured by reference to standard titration curves established previously.
The label is preferably an enzyme. The substrate for the enzyme may be colour-forming, fluorescent or chemiluminescent.
It is highly preferable to use an amplified form of assay, whereby an enhanced ""signal.' is produced from a is relatively low level of protein to be detected. One particular form of amplified immunoassay Is enhanced chem! luminescent (ECL) assay. Here, the antibody is preferably labelled with horseradish peroxidase, which participates in a chemiluminescent reaction with luminol, a peroxide substrate and a compound which enhances the intensity and duration of the emitted light, typically 4iodophenol or 4-hydroxycinnamic acid.
Another preferred form of amplified immunoassay is imm,iino-PCR. In this technique, the antibody is covalently linked to a molecule of arbitrary DNA comprising PCR primers, whereby the DNA with the antibody attached to it is amplified by the polymerase chain reaction. See Hendrickson, E.R. et al., Nucleic Acids Research 23, 522-529 (1995) or Sano, T. et al., in "'Molecular Biology and Biotechnology" ed. Robert A. Meyers, VCH Publishers, Inc. (1995), pages 458 - 460. The signal is read out as before.
In a particularly preferred procedure, an enzymelinked immunosorbent assay (ELISA) was developed to 7 - detect H-FABP in serum. Since H-FABP is a marker for AMI as well, Troponin-1 or CK-MB levels were assayed in order to exclude any heart damage. As described in the Example, these assays were assessed in serial plasma and CSF samples, from patients lacking AMI and WD, patients with AMI patients with dementia and patients with confirmed WD through autopsy. The sensitivity, specúfIcity and predictive accuracy for H-FABP in WD above a suitable cut-off level were all 100%. Thus, H- FABP detection combined with the Troponin-I or CK-MB assay provides a useful serum marker of WD diagnosis or brain damage.
The use of a rapid microparticle-enhanced turb:LcL-Imetric immunoassay, developed for H-FABP in the is case of AMI, Robers, M. et al., "Development of a rapid microparticle- enhanced turbldlmetric immunoassay for plasma fatty acid-binding protein, an early marker of acute myocardial infarctionll, Clin. Chem. 44, 1564- 1567 (1998), should drastically decrease the tIme, of the assay. Thus, the full automation in a widely used clinical chemistry analyser such as the COBASTM MIRA Plus system from Hoffmann-La Roche or the AxSYWm system from Abbott laboratories should be possible and applied for routine clinical diagnosis of WD.
The H-FABP or B-FABP can be measured by other means than immunoassay. For example, the sample can be subjected to 1 or 2-DE gel electrophoresis and the amount of the FABP estimated by densItometric scanning of the gel or of a blot therefrom.
The assay of the invention can be used together with one or more other pre-mortem assays for the TSE, including specifically those assays described above. Such combined procedures are particularly useful in diagnosing BSE in cattle.
The following Example illustrates the invention. EXAMPLE Materials And Methods Patients The study population consisted of 3 age-and-gender matched control patients (Control group), 3 confirmed AMI patients (AMI group), 3 confirmed dementia patients (dementia group) and 3 confirmed WD patients (WD group). The Control group included 2 men, mean age 66, range 46-86 years, and 1 woman, age 63 years. The AMI group included 2 men, mean age 65, range 40-90 years, and 1 woman, age 72 years. The dementia group included 2 men, mean age 65, range 43-87 years, and 1 women, age 64 years. The WD group included 2 men, mean age 68, range 62-74 years, and 1 woman, age 65. Blood and CSF samples were collected for each patient of the WD. Blood samples were collected in dry heparin-containing tubes. After centrifugation at 1500g for 15min at 40C, tubes were stored at -200C until analysis. Patients from the WD group underwent serial clinical evaluations by neurologists in order to confirm WD diagnosis. Patients from the AMI group were admitted to the hospital with a conf Irmed AMI (Troponin-I concentration >2ng/m1). A clinical evaluation was performed on all the patients from the control group to exclude WD and AMI.
Measurement of brain and heart H-FABP H-FABP levels were measured in plasma by a sandwich ELISA. A 96-well polystyrene microplate (NUNC) was coated with 100pl/well goat anti human- FABP, detecting all isoforms (Spectral Diagnosis HC, Ontario, USA), 20.4ng/ml in carbonate buffer 0.1M pH 9.6, overnight at 40C. The plate was automatically washed with PBS (15mM Na2P04-12OmM NaCI-2.7mM KCl pH 7.4, Sigma) on a BioRad NOVAPATH' washer. Every washing step was performed with fresh PBS.
Non-spec fic binding sites were blocked with 200pl/well 2% casein in carbonate buffer for 2h at 3VC. After the washing step, the samples were pipetted in duplicate at 100pl/well. The plate was incubated 2h at 370C. After the washing step, 100pl/well of mouse ant:i-human Heart FABP (clone 66E2, By,Cult Biotechnology BV, Uden, Netherlands), 0.3ng/ml in PBS-1%BSA, were incubated for 1h at room temperature (R.T) with shaking. After the washing step, 100pl/well of phosphatase-labelled anti-mouse immunoglobulin (Dako, Denmark), 15ng/ml in PBS, were incubated 1h 30min at R.T. with shaking. After the washing step, 501A/well of phosphatase substrate, I.Smg/ml para-nitrophenylphosphate in diethanolamine was added and the samples were then incubated for 30min. The is reaction was stopped with 100pl/well IM NaOH. Colour development was measured with a microplate reader at a wavelength of 405nm. CK-MB and Troponin-I measurement AMI was diagnosed by clinical evaluation and Troponin-I and CK-MB measurements. Samples were centrifuged at 1500g for 15min, and stored at -20'C.
Serum CK-MB and Troponin-I levels were determined using a fluorescent microparticle enzyme immunoassay (MEIA) with an automated chemical analyser AxSYW" system (Abbott Laboratories, Abbott Park, IL, USA). The rate of formation of fluorescent products was directly proportional to the amount of Troponin-I in the sample.
The detection limit for TroponIn-I was 0.3pg/1. CK-MB measurement is proportional to the amount of fluorescent probes and the detection limit was 0.7pg/1.
Statistical analysis H-FABP levels were expressed in optical densitometry (M) values either as mean SD or as median and inter- quartile range. Troponin-I and CK-MB levels were - 10 expressed in concentration units (ng/ml). The nonparametric Mann-Whitney U-test and Kruskal-Wallis H-test were used to compare in plasma H-FABP, Troponin-I and CK- MB concentrations between groups. PRISM software was used to elaborate box/whisker and scatter plots. The 95% confidence intervals (CI) and Receiver Operating Characteristic (ROC) curves, defined by Analyse-itIlm software for Microsoft EXCEL", were used to assess the discriminatory time point of the indicators. See Murphy, J.M. et al., "Performance of screening and diagnostic tests", Arch. Gen. Psychiatry 44, 550-555 (1987).
P<0.05 was considered statistically significant. Results Clinical characteristics Patients from the WD group were given a complete clinical evaluation. WD was finally diagnosed with the help of brain immuno-histology after autopsy. Patients from the Control group were admitted to hospital and WD and AMI were excluded by clinical evaluation.
Patients from the AMI group were admitted to the hospital with confirmed AMI with high Troponin-I levels (>2ng/ml).
Assay results are shown in Table 1 below.
Assay Control AMI Dementia WD WD type Group Group Group Group Group plasma plasma CSF plasma CSF H-FABP median 0.25 2.89 0.20 0.79 0.46 (25-75%) (0.23- (2.70- (0.16- (0.74- (0.38- OD, 405 nm 0.27) 3.0) 0.31) 0.86) 0.54) Troponin-1 median 0 50 0 0 0 (25-75%) (0.0_ (50-359) (0.0-0.2 (0.0-0.2) (0.0-0.2) IU ng/ml 0.0) 11 - H-FABP plasma levels (OD measurement) in the AMI group were significantly higher than the respective level in the Control group (Table 2). The ANI group had a HFABP median level (range 25-75%) of 2.89 (2.70-3.0) while the Control group had a level of 0.25 (0.23-0.27). The HFABP plasma level in the WD group was between the slopes of the AMI and the Control groups. H-FABP median (range 25-75%) level in the plasma WD group was 0.79 (0.74- 0.86). The sensitivity, spec-if;iclty, and predictive accuracy of H-FABP levels beyond the cut off value of 0.30 were 100%, 100% and 100% respectively. To confirm differences in H-FABP concentrations between AMI and Control groups, Troponin-1 was assayed. In addition, in order to discriminate AMI and WD, they were also assayed on WD samples. The Troponin-1 concentration was measured in each group. Troponin-I concentration in the AMI group was significantly (p>0.01) higher than in the Control group.
D-iscusslon The above results indicate that H-FABP is a potential marker for WD diagnosis. Since H-MBP was presented as a marker of acute myocardial infarction a few years ago, WD and AMI had to be discriminated by another AMI biochemical marker such as Troponin-I or CKMB. Aúter the discrimination of AMI for WD patient, the serum as well as the CSF H-FABP concentration could be used as a specific marker of WD.
In the present study, H-FABP assay allowed a sensitivity, a specificity and a predictive accuracy (OD response > 0.30) of 100%. These values were significantly higher than those of 14-3-3 protein for detection of WD as the three dementia patients were positive after immilnoblottúng detection. The specIficity of 14-3-3 is not limited to WD but includes also Alzheimer's dementia, cerebral complications from head injury and some other forms of dementia.
Acute myocardial infarction is diagnosed with the help of biochemical marker assays such as cardiac Troponin-I, Creatine-Kinase MB, myoglobin and recently HFABP assay. The H-FABP level for WD could interfere with AMI and discrimination between AMI and WD was made with the use of other AMI markers.
Each of the above cited publications is herein incorporated by reference to the extent to which it is relied on herein.
The following claims define some important is embodiments of the invention, but should not be construed as detracting from the generality of the concepts hereinbefore set forth.
13 -
Claims (8)
1. A method of diagnostic assay for a transmissible spongiform encephalopathy (TSE) or the possibility thereof in a sample of body fluid taken from a patient suspected of suffering from the TSE, which comprises determining the concentration of heart or brain fatty acid binding protein (H-FABP or B-FABP) In the sample.
2. A method according to Claim 1, wherein the subject is a human and the concentration of H-FA.BP is determined in a first assay, whereby a positive result indicates either a WD or acute myocardúal infarction, and which further comprises carrying out a second diagnostic assay, for acute myocardial infarctúon (AMI) only, whereby a is positive result in the H-FABP assay and a negative result in the assay for AMI indicates that the patient is or might be suffering from a WD.
3. A method according to Claim 2, wherein the assay for AMI comprises determining the concentration of troponin-1 or creatine kúnase NB in plasma.
4. A method according to Claim 1, 2 or 3, wherein an antibody to H-FABP is used in the assay for H-FABP.
5. A method according to Claim 4, wherein the subject is a human patient and a mouse anti-human FABP monoclonal antibody is used.
6. A method according to any Claim 4 or 5, wherein the assay for H-FABP comprises a sandwich ELISA.
7. A method according to Claim 1, wherein B-FABP or an antibody thereto is used without any assay for AMI in combination therewith.
8. A method according to any preceding Claim, wherein the H-FABP or BFABP assay is carried out on a blood or serum sample.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0005683A GB2360089A (en) | 2000-03-10 | 2000-03-10 | Diagnostic assay for transmisible spongiform encephalopathies |
GB0006064A GB0006064D0 (en) | 2000-03-10 | 2000-03-14 | Diagnostic assay for transmissable spongiform encephalopathies |
PCT/EP2001/002894 WO2001067108A2 (en) | 2000-03-10 | 2001-03-12 | Diagnostic assay for transmissible spongiform encephalopathies |
AU2001258282A AU2001258282B2 (en) | 2000-03-10 | 2001-03-12 | Diagnostic assay for transmissible spongiform encephalopathies |
DK01931527T DK1261875T3 (en) | 2000-03-10 | 2001-03-12 | Diagnostic analysis for transmissible spongiform encephalopathy |
DE60129674T DE60129674T2 (en) | 2000-03-10 | 2001-03-12 | PROCESS FOR THE DIAGNOSIS OF TRANSMISSIBLE SPONGIFORMS ENCEPHALOPATHIES |
CA002402314A CA2402314C (en) | 2000-03-10 | 2001-03-12 | Diagnostic assay for transmissible spongiform encephalopathies |
JP2001566030A JP4575635B2 (en) | 2000-03-10 | 2001-03-12 | Diagnostic assays for infectious spongiform encephalopathy |
EP01931527A EP1261875B1 (en) | 2000-03-10 | 2001-03-12 | Diagnostic assay for transmissible spongiform encephalopathies |
AU5828201A AU5828201A (en) | 2000-03-10 | 2001-03-12 | Diagnostic assay for transmissible spongiform encephalopathies |
AT01931527T ATE368858T1 (en) | 2000-03-10 | 2001-03-12 | METHOD FOR DIAGNOSING TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES |
US10/238,557 US7368247B2 (en) | 2000-03-10 | 2002-09-10 | Diagnostic assay for transmissible spongiform encephalopathies |
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GB0006064A Ceased GB0006064D0 (en) | 2000-03-10 | 2000-03-14 | Diagnostic assay for transmissable spongiform encephalopathies |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2379737A (en) * | 2001-09-05 | 2003-03-19 | Univ Geneve | Diagnostic method for spongiform encephalopathy disease |
JP2013092538A (en) * | 2005-07-14 | 2013-05-16 | Univ De Geneve | Diagnostic method for brain damage-related disorder |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023962A1 (en) * | 1996-11-23 | 1998-06-04 | Proteome Sciences Plc | Diagnosis of prion diseases |
EP0861900A1 (en) * | 1997-02-21 | 1998-09-02 | Erziehungsdirektion Of The Canton Zurich | Immunological detection of prions |
WO1998045440A1 (en) * | 1997-04-08 | 1998-10-15 | Incyte Pharmaceuticals, Inc. | Human fatty acid binding protein |
-
2000
- 2000-03-10 GB GB0005683A patent/GB2360089A/en not_active Withdrawn
- 2000-03-14 GB GB0006064A patent/GB0006064D0/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023962A1 (en) * | 1996-11-23 | 1998-06-04 | Proteome Sciences Plc | Diagnosis of prion diseases |
EP0861900A1 (en) * | 1997-02-21 | 1998-09-02 | Erziehungsdirektion Of The Canton Zurich | Immunological detection of prions |
WO1998045440A1 (en) * | 1997-04-08 | 1998-10-15 | Incyte Pharmaceuticals, Inc. | Human fatty acid binding protein |
Non-Patent Citations (2)
Title |
---|
J. Neurochem.; Vol 66 (4), pp 1648-1656 (1996). Myers-Payne et al * |
Mol. Cell. Biochem.; Vol 198(1&2), pp 69-78 (1999). Pu et aL * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2379737A (en) * | 2001-09-05 | 2003-03-19 | Univ Geneve | Diagnostic method for spongiform encephalopathy disease |
JP2013092538A (en) * | 2005-07-14 | 2013-05-16 | Univ De Geneve | Diagnostic method for brain damage-related disorder |
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GB0006064D0 (en) | 2000-05-03 |
GB0005683D0 (en) | 2000-05-03 |
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