WO1999042826A1 - Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins - Google Patents
Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins Download PDFInfo
- Publication number
- WO1999042826A1 WO1999042826A1 PCT/US1998/002649 US9802649W WO9942826A1 WO 1999042826 A1 WO1999042826 A1 WO 1999042826A1 US 9802649 W US9802649 W US 9802649W WO 9942826 A1 WO9942826 A1 WO 9942826A1
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- WIPO (PCT)
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- patient
- bodily fluid
- tissue
- reproductive tract
- preeclampsia
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- 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
- G01N33/689—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 pregnancy or the gonads
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/36—Gynecology or obstetrics
- G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
Definitions
- the present invention relates to a method and an apparatus for screening for reproductive tract inflammation and preeclampsia. More particularly, this invention concerns the method and apparatus for screening for reproductive tract inflammation and preeclampsia which utilize the presence of neutrophil defensins found in bodily fluids and tissues of a patient to indicate that the patient is at risk of having reproductive tract inflammation or preeclampsia.
- Diagnosis is a method of establishing the presence of a particular disease in a patient.
- Limitations of the current diagnostic methods include the high cost of a medical professional performing an invasive examination to take samples, run tests and analyze results as well as the inefficient utilization of the sensitive, yet expensive, diagnostic tests. For example, when polymerase chain reaction testing and ligase chain reaction testing, two standard diagnostic tests for sexually transmitted diseases, are performed, the medical professional must administer the test which results in an average of ten patients testing negative for every one patient that tests positive.
- a diagnostic test is employed only after a screening test indicates that the patient is at risk of having a disease in order to eliminate the unnecessary cost of expensive diagnostic tests.
- Screening is a method of establishing the absence of a particular disease or class of diseases in a patient. When a screening test indicates that a patient does not have a disease, in many cases the need for further diagnostic testing is eliminated. Such screening saves money for patients, health insurance companies and government health programs. In addition, screening provides a way for patients to avoid the discomfort associated with more invasive diagnostic procedures.
- female reproductive tract inflammation include, but are not limited to, intraamniotic infection, pelvic inflammatory diseases and sexually transmitted diseases such as gonorrhea, chlamydia and trichomoniasis.
- Pelvic inflammatory diseases may be caused by anaerobic bacterial infection, allergic reactions or prior infection by a sexually transmitted disease. In general the majority of pelvic inflammatory diseases are not symptomatic and therefore, go undetected. If undetected and untreated, pelvic inflammatory diseases may result in tubal factor infertility. Screening for upper reproductive tract inflammation such as salpingitis, cervicitis, endometritis and oophoritis generally includes a pelvic exam conducted by a physician. If manipulation of the cervix and palpitation of the adnexa produces severe pain during the pelvic exam, the patient is considered to be at risk for pelvic inflammatory disease.
- a diagnosis of pelvic inflammatory disease may be obtained by performing an endometrial biopsy or operative laparoscopy both of which are highly invasive and uncomfortable procedures conducted by a physician.
- Intraamniotic infection is an infection of the amnion or amniotic fluid by any pathogen, and is thought to be a significant cause of idiopathic preterm labor which results in preterm deliveries. Screening for intraamniotic infection involves identifying patients in preterm labor.
- the standard diagnostic test for intraamniotic infection involves amniocentesis and growing a culture from the extracted amniotic fluid. Because a culture must be grown, diagnosis may take several days and is expensive. Further, diagnosis is often negative in cases where there is significant placental infection or inflammation.
- Preeclampsia an endothelial cell disorder of unknown etiology, occurs in five to seven percent (5-7%) of pregnant women. If undetected and untreated the condition may lead to stillbirth, premature birth, eclampsia or maternal death.
- the diagnosis of preeclampsia is based on the triad of hypertension, proteinuria and edema.
- the only known treatment for preeclampsia is delivery of the infant. This is unfortunate because many women with preeclampsia are preterm thereby requiring delivery of a premature infant having the potential for serious neonatal sequelae.
- screening methods to identify those destined to develop preeclampsia would help to study potential treatments aimed at preventing disease manifestations.
- the typical screening method for sexually transmitted diseases comprises identifying patients having dysuria and abnormal discharge and the medical practitioner observing whether there is redness, swelling or sores in the genitalia. Additional screening methods include using the leukocyte esterase dipstick or neutrophil quantification on gram chain. Unfortunately these methods have sub-optimal sensitivities and specificities.
- the World Health Organization and some Third World countries use an algorithm comprising a series of questions to screen for sexually transmitted diseases . Because this screening method is based solely on the answers to the questions and not based on a physical assessment of the patient, the degree of error may be high. Further, because of the scarcity of resources in Third World countries, a precise diagnostic test is not performed in cases where the results of the algorithm do not suggest infection thereby missing many patients who truly are infected.
- Gonorrhea is caused by the gonococcal bacterium Neisseria gonorrhea . If undetected and untreated, gonorrhea can cause postgonococcal nonspecific urethritis, epididymitis, pelvic inflammatory disease, arthritis and possibly death.
- One method for diagnosing gonorrhea involves taking a scraping from a patient and performing a Gram-stained smear on the scraping. A culture is required for females because the Gram-stain test for gonorrhea is considered less reliable for females. The disadvantage of this detection method is that it is time consuming and costly because it requires a physician to administer the test.
- Chlamydia is caused by the bacterium Chlamydia trachomatous. If undetected and untreated, chlamydia can cause pelvic inflammatory disease, infertility, ectopic pregnancy and chronic pelvic pain. In addition, undetected chlamydia is thought to cause about fifty percent (50%) of the nonspecific sexually transmitted infections, including nongonococcal urethritis and nonspecific urethritis.
- a standard method for diagnosing chlamydia involves taking a scraping from a patient which in women, is obtained from the endocervix. The specimen is then placed in a sterile nutritive medium and observed under a microscope for signs of microbial growth and the disease organism. Limitations of this diagnostic method include prolonged incubation, cost and sensitivity of only seventy- five percent (75%) to eighty-five percent (85%) .
- the scraping may also be subject to antigen detection tests, such as direct fluorescent antibody testing (DFA) and enzyme-linked immunosorbent assay (ELISA) to detect the pathogenic microbial proteins.
- DFA direct fluorescent antibody testing
- ELISA enzyme-linked immunosorbent assay
- Other antigen detection methods for the diagnosis of chlamydia include serological tests involving either complement fixation or microimmunofluorescence. Though antigen detection tests for chlamydia are easily performed and are less costly than cultures however, they have lower sensitivities than cultures and low positive predictive values in low prevalence populations .
- Trichomoniasis is caused by the flagellate protozoan Trichomonas vaginalis. If undetected and untreated trichomoniasis can cause vaginitis, urethritis, cystitis and prostatitis.
- the current gold standard for the diagnosis of trichomoniasis is culture on a specimen from the posterior fornix. Although highly sensitive, laboratory availability is limited; therefore, wet mount microscopy conducted on a similar specimen from the posterior fornix is most often used to diagnose this condition. The disadvantage of using this diagnostic test to detect trichomoniasis is that it has a sensitivity of only about fifty percent (50%) .
- Newer techniques for detecting Neisseria gonorrhoea, Chlamydia tracho atous and Trichomonas vaginalis rely on nucleic acid amplification with subsequent detection. These methods are termed polymerase chain reaction and ligase chain reaction and are considered the most accurate diagnostic methods available. Although commercially available for Chlamydia trachomatous they will soon be available for Neisseria gonorrhoea and are under development for Trichomonas vaginalis. One important aspect of these methods is there reliance only on the presence of a small amount of organism and not in the viability of the organism.
- neutrophil defensins are elevated in blood plasma in patients with either bacterial meningitis or septicemia. This type of method is described in greater detail in Journal of Laboratory Clinical Medicine; volume 122 at pp 202-7 (1993) .
- the method of detecting female reproductive tract inflammation and preeclampsia disclosed in the present invention which uses the presence of neutrophil defensins found in bodily fluids and tissues such as vaginal fluids or amniotic fluids has never been disclosed or suggested.
- the present invention provides a detection method for reproductive tract inflammation and preeclampsia which combines the accuracy of conventional diagnostic techniques with the convenience and low cost of screening . techniques .
- the present invention provides a method and apparatus for screening for reproductive tract inflammation and preeclampsia which utilizes the presence of increased levels of neutrophil defensins in bodily fluids or tissue extracted from an animal or human patient to indicate that the patient is at risk of having reproductive tract inflammation or preeclampsia.
- neutrophil defensins are highly stable and are abundant in human fluids, the method of the present invention is relatively uncomplex.
- Defensins also known as human neutrophil peptides (HNP) , are cysteine-rich antimicrobial peptides specific to the azurophilic granules of the neutrophil. They constitute greater than five percent (5%) of the total cellular protein and thirty percent (30%) to fifty percent (50%) of the total granule protein.
- Neutrophil defensins are highly stable to prolonged storage and are resistant to proteolysis and pH effects.
- the present invention further provides for the screening of upper reproductive tract inflammation, by measuring neutrophil defensin levels in a specimen extracted from either the endocervical region or vaginal region with the use of a swab or dipstick. This method is more precise than a pelvic exam alone and less expensive and time consuming than a Gram-stain or a culture.
- the present invention allows patients who do not have a pelvic inflammatory disease to avoid the invasive and expensive diagnostic procedure of endometrial biopsy.
- the present invention may also be used to detect intraamniotic infections.
- Amniotic fluid is withdrawn by amniocentesis, and defensin levels within the extracted amniotic fluid are detected. This is faster than the conventional method of culturing amniotic fluid.
- the present invention also provides for screening for preeclampsia by detecting neutrophil defensins in plasma.
- the present invention provides for the detection of preeclampsia in "low-risk" patients prior to the development of clinical symptoms. This may allow for the development of effective treatments to prevent the condition or earlier interventions to prevent the maternal/fetal morbidity associated with clinical presentation.
- the present invention tests vaginal and cervical fluid samples for elevated antimicrobial peptide levels. It is preferred that the sample be taken from the vaginal introitus. By taking the sample from the vaginal introitus rather than the conventional site of the endocervix, the sample can be taken without the use of a speculum and without the aid of medical professionals. This results in the screening method being inexpensive and being accurate.
- the present invention further provides an apparatus which allows the patient to take the sample, run the test and use the results to decide if further diagnostic testing is necessary. Because self-testing avoids involvement by medical professionals it is inexpensive and convenient. Self-testing also saves time because it does not require the use of a laboratory with its time-consuming shipping and record-keeping requirements. In addition, the present invention give results within a few minutes, whereas a laboratory test may take several weeks.
- Figure la is a cross-sectional view of a swab containing a specimen being immersed into a solution in accordance with the present invention.
- Figure lb is an elevational view of the dipstick of the present invention.
- Figure lc is a cross-sectional view of the dipstick shown in Figure lb immersed in the solution containing the specimen shown in Figure la.
- Figure 2a is an elevational view of the dipstick shown in Figure lb wherein the dipstick indicates a positive test.
- Figure 2b is an elevational view of the dipstick shown in Figure lb wherein the dipstick indicates a negative test.
- Figure 2c is an elevational view of the dipstick shown in Figure lb wherein the dipstick indicates a faulty test.
- Graph 1 illustrates the defensin levels measured in vaginal fluids of women.
- Graph 2 illustrates the defensin levels measured in cervical samples of women.
- Graph 3 illustrates the defensin levels measured in endocervical samples of women.
- Graph 4 illustrates defensin levels measured in amniotic fluids of women.
- Graph 5 illustrates defensin levels measured in plasma of both preeclamptic and control women.
- this invention is suitable for other uses, such as detecting reproductive tract infections in male humans and other animals, it will be described as being used to detect reproductive tract inflammation and preeclampsia in females. Such description is for purposes of explanation and is not intended to limit the scope of this invention.
- the antimicrobial peptides whose levels are measured are the defensins known as human neutrophil peptides 1, 2 and 3 (HNP1-3) .
- Defensins are neutrophil granule products that are highly stable to prolonged storage and resistant to proteolysis and pH effects. In the presence of infection, neutrophils are the initial cell recruited to the site of inflammation. Once present they attack and ingest the
- defensins are abundant in patients with infections, intraamniotic infection and preeclampsia and because they are stable, defensins are easier to detect than other neutrophil products.
- defensins such as HNP1-3 are specific to neutrophil and therefore are more specific to inflammatory diseases than many other peptides, such as leukocyte esterase.
- the preferred method of measuring HNP1-3 in a sample of bodily fluid or tissue is by an antigen detection method termed enzyme-linked immunosorbent assay (ELISA) .
- Enzyme- linked immunosorbent assay is preferred because of its enhanced sensitivity to small amounts of peptides.
- the monoclonal antibodies needed for the enzyme-linked immunosorbent assay can be prepared using hybridoma preparation techniques that can be derived from known secreting hybridomal cell lines such as those available from Panyutich et al . which are specific to defensins. This technique is a mini-plate based assay which utilizes monoclonal antibody D-1-1 to capture defensins followed by detection with a monoclonal antibody Dl-11 which is labelled with biotin.
- the monoclonal antibody D-1-1 and Dl-11 are further described in Panyutich et al . , An Enzyme Immunoassay For Human Defensins. J. Immunol. Meth. 1991; 141:149-155.
- the monoclonal antibody D-1-1 is deposited with the American Type Tissue Collection in Bethesda and identified by accession number HB 11462.
- Enzyme-linked immunosorbent assay is further described in European Journal of Immunology, Kohler et al . , Volume 6 at p 292, (1976) .
- screening for sexually transmitted diseases such as gonorrhea, chlamydia and trichomoniasis may be accomplished by the patient using a home test kit in the form of a
- the dipstick-based assay home test kit measures the levels of any one or combination of HNP1-3 in samples taken from the vagina.
- the home test kit is provided with a swab 10 having a tip 12 in order that a specimen can be taken from the vaginal area of the patient.
- the home kit further has a phosphate buffered salient solution 14 contained within a receptacle 14 and a dipstick 18 having a control site 20 and a test site 22, both indicated by hidden lines.
- the control site is labeled non-specifically with your detection apparatus and should change color when the dipstick is utilized. However, if a specimen or solution 14 is faulty, the control site will not change color.
- the test site 22 is treated with an amount of monoclonal antibody Dl-1 such that if the specimen contains a level of HNP1-3 below the cut-off point it will not change color. However if it contains a level of defensins above the cutoff point it will change color.
- the swab 10 is immersed in the phosphate buffered solution 14 such that the solution 14 contains the specimen.
- the dipstick 18 is then immersed in the phosphate buffered solution 14 containing the specimen.
- the dipstick 18 is extracted from the solution 14 and one of the three scenarios shown in Figure 2 will result.
- Both the test site 22 and the control site 20 may change color as shown in Figure 2a which would indicate that the patient tested positive meaning that the patient is at risk of having the sexually transmitted disease.
- a negative reading may be obtained when the control site 20 changes color and the test site 22 does not change color.
- a negative reading indicates that the patient is not at risk of having the sexually transmitted disease and there is no need to undergo expensive diagnostic tests.
- the last possible scenario is shown in Figure 2c wherein neither the
- control site 20 nor the test site 22 changes color indicating that a faulty test. In this instance, the patient or doctor should administer the test again. It is preferred that the means for extracting the specimen be able to store the specimen such that the specimen is able to be transferred to a laboratory for further diagnostic testing.
- the home test kit may take a similar form to that of any of the conventional home pregnancy tests.
- the likely antibody congugales will be colloidal gold or latex beads .
- the preferred method of the invention comprises extracting a sample of bodily fluid or tissue from a patient, measuring the amount of antimicrobial peptides in the sample preferably by enzyme-linked immunosorbent assay or dipstick assay, comparing the amount of HNP1-3 with a known normal level and indicating to the patient if the sample contains an amount of HNP1-3 that exceeds the known normal level which signifies that the patient is at risk of having a sexually transmitted disease.
- the vagina is the preferred test site for several reasons. First, it is a less invasive site than other test sites, such as the cervix. Second, a vaginal test site allows for self-testing with the home test kit. Finally, the vagina is a preferred test site because there is a pronounced difference in the level of HNP1-3 for each type of sexually transmitted disease measured.
- vaginal and cervical fluids were measured in vaginal and cervical fluids of 300 women presenting for sexually transmitted disease evaluation at a county health department and the results are presented in Graph 1 and Graph 2, respectively.
- HNPl-3 in vaginal samples may not only be used as a screen for sexually transmitted diseases in general, but as an indicator of which sexually transmitted disease a woman might have. If the present invention screening method indicates that the patient is at risk of having a sexually transmitted disease, the stability of defensins would allow the patient, without visiting a health provider, to send the sample of vaginal fluid to a lab for a precise diagnosis. This indication would help steer the laboratory or health provider to the correct diagnostic test for confirmation of a particular sexually transmitted disease, and lead to lower costs, faster diagnosis and, ultimately, faster treatment.
- screening for upper reproductive tract inflammation such as endometritis is accomplished by measuring levels of HNPl-3 in a sample taken from the endocervix. This would replace the need for the highly invasive endometrial biopsy or
- diagnosis of intraamniotic infection is accomplished by measuring levels of HNPl-3 in a sample of amniotic fluid.
- Amniotic fluid HNPl-3 levels of 53 patients presenting in preterm labor were measured and the results thereof are depicted in Graph 4.
- median HNPl-3 levels were 1,351.50 ng/ml with a standard error of 29,379 ng/ml.
- Patients who were not infected had median HNPl-3 levels of 49 ng/ml with a standard error of 16.89 ng/ml. Descriptive statistics utilizing a cut point of 400 ng/ml are also presented.
- screening for preeclampsia is accomplished by measuring levels of HNPl-3 in plasma. Defensin levels in preeclamptic patients were compared with those in control patients who delivered at term without preeclampsia and the results are depicted in Graph 5. Control patients without preeclampsia had median HNPl-3 levels of 9 ng/ml, with a standard error of 8.6. Patients who had preeclampsia had median HNPl-3 levels of 26 ng/ml with a standard error of 16.2. Descriptive statistics using a cut point of 25 ng/ml are also presented.
- the present invention provides for the above procedures may be used to detect HNP4 levels or other members of the defensin family, either alone or in combination with HNPl-3. Further the present invention can also be utilized to measure HNP levels in various other samples not described above such as mucosal samples taken from men or other animals to screen for reproductive tract disease.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98907427A EP1051615A4 (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
PCT/US1998/002649 WO1999042826A1 (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
AU63235/98A AU6323598A (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
CA002296022A CA2296022A1 (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/US1998/002649 WO1999042826A1 (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
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WO1999042826A1 true WO1999042826A1 (en) | 1999-08-26 |
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PCT/US1998/002649 WO1999042826A1 (en) | 1998-02-06 | 1998-02-06 | Screening method for reproductive tract inflammation and preeclampsia using neutrophil defensins |
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Country | Link |
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EP (1) | EP1051615A4 (en) |
AU (1) | AU6323598A (en) |
CA (1) | CA2296022A1 (en) |
WO (1) | WO1999042826A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006021673A3 (en) * | 2004-08-06 | 2006-04-20 | Tycoon R & D Ltd | Markers and methods for prenatal screening of chromosomal aberrations |
CN100335126C (en) * | 2003-08-18 | 2007-09-05 | 上海高科生物工程有限公司 | Preparation for preventing and curing endometritis for dairy cattle and preparing method thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5126257A (en) * | 1986-11-26 | 1992-06-30 | Cornell Research Foundation | Antimicrobial proteins, compositions containing same and uses thereof |
US5459235A (en) * | 1993-03-19 | 1995-10-17 | The Regents Of The University Of California | Antimicrobial peptides antibodies and nucleic acid molecules from bovine neutrophils |
US5556782A (en) * | 1993-06-30 | 1996-09-17 | Board Of Supervisors Of Louisiana State University And Agricultural & Mechanical College | Transformed mammalian cells capable of expressing cecropin b |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI92882C (en) * | 1992-12-29 | 1995-01-10 | Medix Biochemica Ab Oy | Disposable test strip and process for its manufacture |
-
1998
- 1998-02-06 AU AU63235/98A patent/AU6323598A/en not_active Abandoned
- 1998-02-06 CA CA002296022A patent/CA2296022A1/en not_active Abandoned
- 1998-02-06 WO PCT/US1998/002649 patent/WO1999042826A1/en not_active Application Discontinuation
- 1998-02-06 EP EP98907427A patent/EP1051615A4/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5126257A (en) * | 1986-11-26 | 1992-06-30 | Cornell Research Foundation | Antimicrobial proteins, compositions containing same and uses thereof |
US5459235A (en) * | 1993-03-19 | 1995-10-17 | The Regents Of The University Of California | Antimicrobial peptides antibodies and nucleic acid molecules from bovine neutrophils |
US5556782A (en) * | 1993-06-30 | 1996-09-17 | Board Of Supervisors Of Louisiana State University And Agricultural & Mechanical College | Transformed mammalian cells capable of expressing cecropin b |
Non-Patent Citations (5)
Title |
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PANYUTICH A.V., ET AL.: "PLASMA DEFENSIN CONCENTRATIONS ARE ELEVATED IN PATIENTS WITH SEPTICEMIA OR BACTERIAL MENINGITIS.", JOURNAL OF LABORATORY AND CLINICAL MEDICINE, vol. 122., no. 02., 1 August 1993 (1993-08-01), pages 202 - 207., XP002913469, ISSN: 0022-2143 * |
PRIETO J.A., ET AL.: "NEUTROPHIL ACTIVATION IN PREECLAMPSIA. ARE DEFENSINS AND LACTOFERRIN ELEVATED IN PREECLAMPTIC PATIENTS?", JOURNAL OF REPRODUCTIVE MEDICINE., JOURNAL OF REPRODUCTIVE MEDICINE, INC., US, vol. 42., no. 01., 1 January 1997 (1997-01-01), US, pages 29 - 32., XP002913466, ISSN: 0024-7758 * |
REBELO I., ET AL.: "COMPARATIVE STUDY OF LACTOFERRIN AND OTHER BLOOD MARKERS OF INFLAMMATORY STRESS BETWEEN PREECLAMPTIC AND NORMAL PREGNANCIES.", EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, ELSEVIER IRELAND LTD., IE, vol. 64., 1 February 1996 (1996-02-01), IE, pages 167 - 173., XP002913467, ISSN: 0301-2115, DOI: 10.1016/0301-2115(95)02334-8 * |
REIN M.F., ET AL.: "USE OF LACTOFERRIN ASSAY IN THE DIFFERENTIAL DIAGNOSIS OF FEMALE GENITAL TRACT INFECTIONS AND IMPLICATIONS FOR THE PATHOPHYSIOLOGY OF BACTERIAL VAGINOSIS.", SEXUALLY TRANSMITTED DISEASES., LIPPINCOTT CO., PHILADELPHIA., US, vol. 23., no. 06., 1 November 1996 (1996-11-01), US, pages 517 - 521., XP002913468, ISSN: 0148-5717 * |
See also references of EP1051615A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100335126C (en) * | 2003-08-18 | 2007-09-05 | 上海高科生物工程有限公司 | Preparation for preventing and curing endometritis for dairy cattle and preparing method thereof |
WO2006021673A3 (en) * | 2004-08-06 | 2006-04-20 | Tycoon R & D Ltd | Markers and methods for prenatal screening of chromosomal aberrations |
Also Published As
Publication number | Publication date |
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CA2296022A1 (en) | 1999-08-26 |
EP1051615A1 (en) | 2000-11-15 |
AU6323598A (en) | 1999-09-06 |
EP1051615A4 (en) | 2002-08-21 |
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